Oncology consititutional Flashcards by Josh Klonoski

What is the detection sensitivity of the revised Amsterdam criteria (Amsterdam II criteria) to the clinical diagnosis of Lynch syndrome?
A. 60%
B. 70%
C. 80%
D. 90%
E. 100%
F.None of the above

C. 80%
At least 3 relatives with Lynch syndrome-associated cancer: This includes colorectal, endometrial, small bowel, ureter, or renal pelvis cancer.
At least 2 successive generations affected:
One first-degree relative of the other two
At least 1 relative diagnosed before age 50
Rule out FAP

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Prenatal care at 6 wks and maternal brother with FAP. The couple wanted to find out the risk of their first unborn child developing FAP. What should be the next step in the workup be to estimate the risk in this family?
A.Testing the wife for the APC gene
B.Recommending CVS to test the fetus for the APC gene
C.Testing the wife’s brother for the APC gene
D.Recommending that the couple test the child after he/she is born E.Recommending amniocentesis to test the fetus for the APC gene

C.Testing the wife’s brother for the APC gene

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Prenatal care at 6 wks and maternal brother with FAP. The couple wanted to find out the risk of their first unborn child developing FAP. Which one of the following assays would most likely be used for the genetic test to establish/rule out genetic etiologies in this family?
A. Chromosome microarray B.Denaturing high-performance liquid chromatography (dHPLC) analysis of the APC gene
C. Exome sequencing
D.Multiplex ligation-dependent probe amplification (MLPA) analysis of the APC gene
E.Next-generation sequencing for hereditary colorectal cancers F.Sequence analysis of the APC gene

F.Sequence analysis of the APC gene

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A 48-year-old male was diagnosed with colon cancer. The family history was uneventful. Which one of the following hereditary cancer syndromes should be ruled out in this patient even with the negative family history?
A.Familial adenomatous polyposis (FAP) B. Juvenile polyposis syndrome
C. Lynch syndrome
D. MYH-associated polyposis
E. Peutz–Jeghers syndrome

C. Lynch syndrome

ALL new CRC

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MLH1 molecular test for female patient, and the results were positive. Which one of the following cancers would this female patient NOT have an increased risk of developing?
A. Endometrial cancer
B. Hepatobiliary tract cancer
C. Lung cancer
D. Ovarian cancer
E. Stomach cancer

C. Lung cancer

NOT lung or breast cancer

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MLH1 molecular test for female patient, and the results were positive. Which one of the following cancers would this female patient NOT have an increased risk of developing?
A. Breast cancer
B. Endometrial cancer
C. Hepatobiliary tract cancer
D. Ovarian cancer
E. Stomach cancer

A. Breast cancer

NOT lung or breast cancer

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Colorectal cancer (CRC). Microsatellite instability (MSI) analyses of the tumor sample showed a high level of MSI. What would be the most likely diagnosis for this patient?
A.Familial adenomatous polyposis (FAP) B. Lynch syndrome
C. MYH-associated polyposis
D. Sporadic colon cancer
E.None of the above

D. Sporadic colon cancer

Approximately 10%–15% of sporadic CRCs also exhibit MSI. The molecular basis for instability in these tumors is most often methylation of the MLH1

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Colorectal cancer (CRC). Microsatellite instability (MSI) analyses of the tumor sample demonstrated MSI in 40% of markers. What would be the most likely diagnosis for this patient?
A.Familial adenomatous polyposis (FAP) B. Lynch syndrome
C. MYH-associated polyposis
D. Sporadic colon cancer
E.None of the above

D. Sporadic colon cancer

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CRC in older male. Which one of the following specimens would be most appropriate for the MSI test in this patient?
A. Buccal swab
B. Peripheral-blood sample
C. Resected tumor tissue
D. Skin tissue
E. Urine sample
F.None of the above

C. Resected tumor tissue

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CRC in older male. Which one of the following microsatellites would most likely demonstrate instability if the patient had Lynch syndrome?
A. A mononucleotide polymorphism
B. A trinucleotide polymorphism
C. A pentanucleotide polymorphism
D. A single-nucleotide polymorphism
E. Unclear

A. A mononucleotide polymorphism

Mononucleotide repeat markers are more likely to be unstable than other microsatellites in mismatch repair (MMR)–deficient tumors. - more likely to be homozygous mono repeats

The MSI Analysis System, Version 1.2, from Promega is a fluorescent multiplex PCR–based method that detects microsatellite instability (MSI) with five mononucleotide repeats, and two pentanucleotide repeats are the identity controls.

The ABI kit is a fluorescent multiplex PCR–based method that detects microsatellite instability (MSI) with five dinucleotide repeats.

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CRC older male. Microsatellite instability (MSI) analyses of the tumor sample showed a high level of MSI. What percentage (or more) of the repeats would be unstable if an MSI-high profile was reported?
A. 20%
B. 40%
C. 60%
D. 80%
E. 100%

B. 40%

An MSI-low profile is reported if fewer than 40% of repeats are unstable.

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Which one of the following type of malignancies, besides colon cancer, has a high incidence of microsatellite instability (MSI)?
A. Cervical cancer
B. Endometrial carcinoma
C. Intestinal cancer
D. Ovarian cancer
E. Stomach cancer

B. Endometrial carcinoma

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How frequently is MSI seen in patients with endometrial carcinoma?
A. <1% B.
5%–10%
C. 20%–30%
D. 40%–50%
E. >90%

C. 20%–30%

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How frequently is microsatellite instability (MSI) seen in Lynch syndrome patients with colorectal carcinoma (CRC) ?
A. <1%
B. 5%–10%
C. 20%–30%
D. 40%–50%
E. >99%

E. >99%

autosomal dominant disease with a population incidence of 1 in 400–500 and is responsible for about 3% of all CRCs.

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The oncologist contacted the pathologist to request microsatellite instability (MSI) analysis to rule out Lynch syndrome. The results showed three of five mononucleotide polymorphisms were unstable. However, it also showed that one of the control pentanucleotide polymorphisms had allele 20/20 in the tumor tissue, while it had alleles 20/24 in the peripheral-blood sample from the patient. Which one of the following statements would be the most appropriate reaction to this result? A.The molecular MSI test did not work; immunohistochemistry staining for MSI is recommended.
B.Repeat the test with the same specimens.
C.Report out as MSI-high profile in the tumor sample with loss of heterozygosity (LOH).
D.Second tumor and peripheral-blood specimens from the same patient should be requested in order to run the test again.
E.The personal identification test should be run on both the tumor and peripheral-blood specimens to confirm that they are from same patient.

C.Report out as MSI-high profile in the tumor sample with loss of heterozygosity (LOH).

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48 yo woman with CRC and a brother diagnosed with colon cancer at age 45 and her mother diagnosed with endometrial cancer at age 50. She also had one unaffected sister. The physical examination was unremarkable. Of which one of the following hereditary cancer syndromes should we be suspicious in this family?
A. Cowden syndrome
B. Li–Fraumeni syndrome
C. Lynch syndrome
D.Multiple endocrine neoplasia type 1 (MEN1)
E. von Hippel–Lindau disease

C. Lynch syndrome

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Which one of the following genetic tests should be done first to rule out genetic etiologies, according to ACMG Technical Standard and Guidelines for Genetic Testings for Inherited CRC, 2014?
A. APC, MUTYH
B.BRAF gene p.V600E mutation
C. Exome sequencing
D. MSI
E.NGS with BMPR1A, SMAD2, STK11, and PTEN
F.NGS with MLH1, MSH2, MSH6, PMS2, and PSM6

D. MSI

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Microsatellite instability (MSI) testing revealed a high level of MSI. Which one of the following genetic tests should be done next to further rule out genetic etiologies, according to the ACMG Technical Standard and Guidelines for Genetic Testings for Inherited CRC, 2014?A. APC, MUTYH
B.BRAF gene p.V600E mutation
C. Exome sequencing
D. Microsatellite instability test
E.NGS with BMPR1A, SMAD2, STK11, and PTEN
F.NGS with MLH1, MSH2, MSH6, PMS2, and PSM6

B.BRAF gene p.V600E mutation

BMPR1A and SMAD4 genes are associated with autosomal dominant juvenile polyposis syndrome. Germline pathogenic variants in the STK11 gene are associated with autosomal dominant Peutz–Jeghers syndrome. Germline pathogenic variants in the PTEN gene are associated with autosomal dominant PTEN hamartomatous tumor syndrome.

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48 yo woman with CRC and a brother diagnosed with colon cancer at age 45 and her mother diagnosed with endometrial cancer at age 50. She also had one unaffected sister.Which one of following assays would be appropriate for this family in order to rule out genetic etiologies?
A. Chromosome microarray
B.Multiplex ligation-dependent probe amplification (MLPA)
C.NGS with BMPR1A, SMAD2, STK11, and PTEN
D.NGS with MLH1, MSH2, MSH6 and PMS2
E.No need for genetic tests

D.NGS with MLH1, MSH2, MSH6 and PMS2
*edited to remove PSM6 typo

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The results demonstrated that the patient had a deleterious pathogenic variant in the PMS2 gene. Which one of following hereditary cancer syndromes did the patient have?
A. Familial adenomatous polyposis
B. Juvenile polyposis syndrome
C. Lynch syndrome
D. MYH-associated polyposis
E. Peutz–Jeghers syndrome

C. Lynch syndrome

Lynch syndrome most common inherited CRC. 1in 500 and 3% of CRCs. Patients with Lynch syndrome have up to an 80% lifetime risk of developing colon cancer. Women with Lynch syndrome have up to a 60% lifetime risk of developing endometrial carcinoma. Affected individuals are also at greater risk for other cancers, such as stomach, ovarian, small bowel, biliary, renal pelvis, and ureteral cancers.

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Most individuals with LS have a germline pathogenic variant in one of the DNA mismatch repair genes. Which one of following genes is NOT a mismatch repair gene?
A. APC
B. MLH1
C. MLH3
D. MSH6
E. PMS1

A. APC

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Which one of following genes is associated with Lynch syndrome, but is NOT a mismatch repair gene?
A. EpCAM
B. MLH1
C. MLH3
D. MSH6
E. PMS1
F. PMS2

A. EpCAM

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The results demonstrated the patient had a deletion in the EpCAM gene. Which one of following microsatellite instability (MSI) findings would this patient most likely have?
A. MSI-high
B. MSI-low
C. MSI-stable
D. Not sure
E. None of the above

A. MSI-high

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The results demonstrated the patient had a deletion in the EpCAM gene. Which one of following immunohistochemistry (IHC) findings would this patient have? A.Loss expression of MLH1 and MSH2 B.Loss expression of MLH1 and PMS2 C.Loss expression of MSH2 and MSH6 D.Loss expression of MSH2 and PMS2 E.None of the above

C.Loss expression of MSH2 and MSH6

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Paternal CRC and paternal aunt UEC. The physical examination was unremarkable. Which one of the following genes would most likely NOT provide information to confirm or rule out genetic etiologies in this patient? A. MLH1 B. MSH2 C. MSH3 D. MSH6 E. PMS2

C. MSH3

The results showed no staining for MHL1 and PMS2, but staining for MSH2 and MSH6. A BRAF mutation test was positive for the V600E mutation. Which one of the following mutations is most likely detectable in tumor? A. p.Arg134Ter in PMS2 B. Promoter hypermethylation in PMS2 C. p.Pro622Leu in MSH2 D. Promoter hypermethylation in MSH2 E. p.Ser252Ter in MHL1 F. Promoter hypermethylation in MHL1

F. Promoter hypermethylation in MHL1

Lynch syndrome is the most common cause of inherited colorectal cancer (CRC), characterized by a significantly increased risk for CRC and endometrial cancer as well as a risk of several other malignancies. Which one of the following DNA mismatch repair genes tends to be hypermethylated in individuals with sporadic CRCs? A. MLH1 B. MLH3 C. MSH6 D. PMS1 E. PMS2

A. MLH1 Approximately 10%–15% of sporadic CRCs also exhibit MSI. The molecular basis for instability in these sporadic tumors is most often methylation of the MLH1 promoter, leading to loss of both mRNA and protein expression

A molecular test confirmed that the patient had a pathogenic variant in the MSH2 gene. Which one of the following malignancies would this patient have the highest risk of developing in her lifetime? A. Cervical cancer B. Endometrial carcinoma C. Hepatocellular carcinoma D. Ovarian cancer E. Stomach cancer

B. Endometrial carcinoma 40-60% risk for both CRC and UEC

A molecular test confirmed the patient had a pathogenic variant in the MSH2 gene. What would be this patient’s risk of developing colorectal cancer in her lifetime? A. 20% B. 40% C. 60% D. 80% E. >99%

D. 80% Patients with Lynch syndrome have up to an 80% lifetime risk of developing colon cancer and, in women, up to a 60% lifetime risk of developing endometrial carcinoma.

A molecular test confirmed the patient had a pathogenic variant in the MSH2 gene. What would be this patient’s risk of developing endometrial carcinoma in her lifetime? A. 20% B. 40% C. 60% D. 80% E. >99%

C. 60% Patients with Lynch syndrome have up to an 80% lifetime risk of developing colon cancer and, in women, up to a 60% lifetime risk of developing endometrial carcinoma.

The results showed no staining for MHL1 and PMS2, but staining for MSH2 and MSH6. Which one of the following would be appropriate next step in the workup for this patient? A. BRAF mutation analysis B. Diagnosing the patient with endometrial adenocarcinoma without genetic etiology C. Diagnosing the patient with Lynch syndrome D. Performing next-generation sequencing for all the genes for hereditary colon cancer E. Performing sequencing analysis of MLH1 and PMS1 F. Performing sequencing analysis of MSH2 and MSH6

E. Performing sequencing analysis of MLH1 and PMS1

The results showed MSI in three of six markers, loss of expression of MSH2, and normal expression of MLH1. Molecular genetic tests of both MSH2 and MSH6 were negative. Which one of the following tests might be the next step in the workup to further rule out Lynch syndrome in this patient? A. A larger next-generation sequencing panel for hereditary colon cancer syndromes B. BRAF gene p.V600E mutation test C. EpCAM gene 3′ deletion test D. MLH1 promoter methylation study E. MLH1 and PMS2 gene-mutation test

C. EpCAM gene 3′ deletion test

The results showed MSI in three of six markers, loss of expression of MSH2, and normal expression of MLH1. Molecular genetic tests of both MSH2 and MSH6 were negative. To further rule out Lynch syndrome in this patient, the medical geneticist ordered a molecular test on the EpCAM gene, and the results turned out to be positive. Which one of the following changes in EpCAM would most likely be detected in this patient? A. Deletion B. Frameshift mutation C. Insertion D. Missense mutation E. Nonsense mutation

A. Deletion

The results showed MSI in three of six markers, loss of expression of MSH2, and normal expression of MLH1. Molecular genetic tests of both MSH2 and MSH6 were negative. To further rule out Lynch syndrome in this patient, the medical geneticist ordered a molecular test on the EpCAM gene, and a deletion on the 3′ end of the gene was detected. How would the deletion in EpCAM cause Lynch syndrome in this patient? A. It causes somatic hypermethylation of MLH1. B. It causes somatic hypermethylation of MSH2. C. It causes somatic hypermethylation of MSH6. D. It causes somatic hypermethylation of PMS2. E. None of the above.

B. It causes somatic hypermethylation of MSH2.

The results of a CRC showed a high level of MSI, loss of expression of MLH1, and normal expression of MSH2. Predictably, which one of the following genes lose expression, too, in the tumor tissue from this patient? A. BRAF B. MSH6 C. PMS2 D. All of the above E. None of the above

C. PMS2

The results showed high level of MSI, loss of expression of MSH2, and normal expression of MLH1. Predictably which one of the following genes would lose expression, too, in the tumor tissue from this patient? A. BRAF B. MSH6 C. PMS2 D. All of the above E. None of the above

B. MSH6

The results showed 50% of MSI, loss of expression of MLH1, and normal expression of MSH2. What would be the next step in the workup according to ACMG Technical Standard and Guidelines for Genetic Testing for Inherited CRC, 2014? A. BRAF p.V600E test B. BRAF p.V600K test C. BRAF sequence D. MLH1 and MSH2 sequence E. MLH1 and MSH6 sequence F. MLH1 and PMS2 sequence

A. BRAF p.V600E test

The results showed MSI in three of six markers and loss of expression of MSH2 and MSH6. What would be the next step in the workup according to ACMG Technical Standard and Guidelines for Genetic Testing for Inherited CRC, 2014?A. BRAF p.V600E mutation test B. BRAF p.V600K test C. BRAF sequence D. MSH2 sequence E. MSH6 gene-mutation test F. MSH2 and MSH6 gene-mutation test

F. MSH2 and MSH6 gene-mutation test

48 yo man with adenomatous polyps throughout the colon. His family history was negative for polyposis and/or CRC. What would be the most appropriate molecular test as the next step in the workup to rule out genetic etiologies in this patient? A. Sequence the APC gene with reflex to APC del/dup analysis B. Sequence the MUTYH gene with reflex to MUTYH del/dup analysis C. Sequence the MLH1 gene with reflex to MLH1 del/dup analysis D. Sequence the MSH2 gene with reflex to MSH2 del/dup analysis E. Sequence the APC and MUTYH genes with reflex to APC and MUTYH del/dup analysis F. Sequence the MLH1 and MSH2 genes with reflex to MLH1 and MSH2 del/dup analysis

E. Sequence the APC and MUTYH genes with reflex to APC and MUTYH del/dup analysis absence of family history in MAP and the high rate of de novo mutations in attenuated FAP and FAP (20%), analysis of both MUTYH and APC gene mutations should be considered for patients with or without adenomatous polyps.

All of the following tumors are consistent with Lynch syndrome, EXCEPT: A. BRAF mutation–negative, MLH1 methylation negative, MSI-high colorectal cancer B. MLH1 immunohistochemistry (IHC)–negative, BRAF mutation–positive colorectal cancer C. MSH2 and MSH6 immunohistochemistry (IHC)–negative endometrial adenocarcinoma D. MSI-high, MLH1 methylation–negative endometrial adenocarcinoma E. MSI-high, MLH1 immunohistochemistry (IHC)–negative endometrial adenocarcinoma with three first-degree relatives for either colorectal cancer or endometrial adenocarcinoma

B. MLH1 immunohistochemistry (IHC)–negative, BRAF mutation–positive colorectal cancer BRAF mutation is associated with sporadic colorectal cancers.

Adenomatous polyps throughout the colon. The family history was negative for polyposis and/or CRC. A KRAS mutation analysis showed that the patient had a somatic c.34G>T mutation. Which one of the hereditary cancer predisposition syndromes would this patient most likely have if she had one? A. Familial adenomatous polyposis B. Lynch syndrome C. MYH-associated polyposis D. Peutz–Jeghers syndrome E. PTEN hamartomatous syndrome

C. MYH-associated polyposis FAP is autosomal dominant Germline pathogenic variants in the MUTYH gene are associated with autosomal recessive (AR) MYH-associated adenomatous polyposis (MAP). With the absence of family history in MAP and the high rate of de novo mutations in attenuated FAP and MAP (20%), both FAP and MAP are on the list of differential diagnoses. A molecular hallmark of carcinomas caused by MUTYH deficiency is the presence of a specific somatic KRAS mutation, c.34G>T (G12C) in codon 12 in 64% of MAP CRCs, which does not appear in FAP

A 16-year-old male was referred to a genetics clinic for mild cognitive impairment with >1000 colorectal adenomatous polyps. Genetic evaluations uncovered that he also had mild dysmorphic features. The family history was unremarkable on both sides. The medical geneticist ordered a test to rule out genetic etiologies. Which one of the following genetic tests would be most appropriate for this patient? A. Chromosome microarray B. Methylation study of the APC gene C. Sequence the APC gene D. Sequence the MUTYH gene E. Sequence APC and MUTYH genes F. None of the above

Interstitial deletions of chromosome 5q22 that include APC have been reported in individuals with attenuated adenomatous polyposis and classic adenomatous polyposis. In all reports, such individuals have had cognitive impairment, usually in the mild-to-moderate range, and the majority had dysmorphic features Normal FAP mutations have normal intelligence and appearance

Which one of the following genes associated with Lynch syndrome has more pseudogenes than the others? A. BRAF B. EpCAM C. MLH1 D. MSH2 E. MUTYH F. PMS2

F. PMS2 15 pseudogenes

MSI for CRC patient showed one of five mononucleotide polymorphisms were unstable. Immunohistochemistry (IHC) stains for MLH1, MSH2, PMS2, and MSH6 were done with the tumor tissue. The results showed staining for all four proteins. The patient met the clinical diagnosis for Lynch syndrome based on Amsterdam II Criteria. Which one of the following genes would most likely harbor a pathogenic variant in this patient? A. BRAF B. MLH1 C. MSH2 D. MSH6 E. PMS2

D. MSH6

Clinical diagnosis of juvenile polyposis was made. The medical geneticist ordered a molecular test for this patient. Which gene(s) listed would most likely be included in the genetic evaluations for this patient? A. APC B. BMPR1A C. APC and BMPR1A D. SMAD4 E. BMPR1A and SMAD4 F. STK11 G. APC and STK11

E. BMPR1A and SMAD4 20% BMPR1A and 20% SMAD4

A 13-year-old male patient was referred to a genetics clinic to rule out genetic etiologies for his recurrent GI bleeding, mucocutaneous telangiectases, and pulmonary arteriovenous malformations. His pediatric gastroenterologist found and had been able to control the polyps in the stomach and colon by upper endoscopy and colonoscopy. Histopathological evaluations of the lesions in the upper duodenum demonstrated high-grade dysplasia. Which one of the following analyses would most likely be used for the genetic evaluation to rule out genetic etiologies in this patient? A. Chromosome karyotype B. Microarray copy-number analysis C. APC sequencing D. BMPR1A sequencing E. SMAD4 sequencing F. STK11 sequencing

E. SMAD4 sequencing Juvenile polyposis syndrome/Hereditary hemorrhagic telangiectasias with SMAD4

Upper GI juvenile polyps with colonic hamartomatous poyps with dysplasia. Developmental delay and macrocephaly. Which one of the following analyses would most likely be used for the genetic evaluation to rule out genetic etiologies in this patient? A. Chromosome karyotype B. Microarray copy-number analysis C. APC sequencing D. BMPR1A sequencing E. SMAD4 sequencing F. PTEN sequencing

B. Microarray copy-number analysis 10q22-q23 microdeletion syndrome with PTEN (Cowden - cognition and macrocephaly) and BMPR1A (JPS)

Juvenile patient with strong FHx of CRC and perioral and acral/oral freckles. What one of the following hereditary cancer predisposition syndromes may this patient have if he has one? A. Familial adenomatous polyposis B. Lynch syndrome C. MYH-associated polyposis D. Peutz–Jeghers syndrome E. PTEN hamartomatous syndrome

D. Peutz–Jeghers syndrome

Histopathological examinations revealed hamartomatous polyps consistent with a clinical diagnosis of Peutz–Jeghers syndrome (PJS). Which gene(s) listed below would most likely be included in the genetic test for this patient? A. APC B. BMPR1A C. APC and BMPR1A D. SMAD4 E. BMPR1A and SMAD4 F. STK11 G. APC and STK11

F. STK11 19P13.3- STK11/LKB1 GI hamartomatous polyps and mucocutaneous hyperpigmentation

Histopathological examinations revealed hamartomatous polyps consistent with a clinical diagnosis of Peutz–Jeghers syndrome (PJS). Which one of the following represents the approximate detection rate of sequencing analysis of the STK11 gene in patients diagnosed with PJS clinically? A. 25% B. 50% C. 75% D. 99% E. Unknown

B. 50%

Molecular genetic tests detected a heterozygous pathogenic variant in the STK11 gene. A diagnosis of Peutz–Jeghers syndrome was made. Which one of the following cancers would the patient have highest risk of developing in her lifetime? A. Brain tumor B. Breast cancer C. Cervical cancer D. Melanoma E. None of the above

B. Breast cancer PJS highest risk for GI and breast cancer

A microarray copy-number analysis was ordered for a 4-year-old girl with autism. The results revealed a 324-kb deletion on 19p13.3, including the STK11 gene. What would be the clinical significance of this finding? A. Pathogenic B. Unknown clinical significance, likely pathogenic C. Unknown clinical significance D. Unknown clinical significance, likely benign E. Benign

A. Pathogenic Even if not related to autism - although some evidence deletion can be associated with autism

43 yo with bilateral BRCA, macrocephaly and FHx of endometrial, RCC and "neck" cancer. Which one of the following hereditary cancer predisposition syndromes would this patient most likely have if she had one? A. Familial adenomatous polyposis B. Lynch syndrome C. MYH-associated polyposis D. Peutz–Jeghers syndrome E. PTEN hamartomatous tumor syndrome

E. PTEN hamartomatous tumor syndrome Cowden syndrome (CS) is a type of PTEN hamartomatous tumor syndrome. Affected individuals usually have macrocephaly (>97th percentile head circumference), trichilemmomas, and papillomatous papules. The lifetime risk of developing benign and malignant tumors of the thyroid, breast, and endometrium is increased significantly.

43 yo with bilateral BRCA, macrocephaly and FHx of endometrial, RCC and "neck" cancer. Which one of the following gene-sequencing tests would be the most appropriate first-tier genetic evaluation for this patient? A. BRAC1 B. BRAC2 C. BRAC1 and BRAC2 D. CDH1 E. PTEN F. STK11 G. VHL

E. PTEN

A small-bowel segment was resected. Histopathological examinations revealed hamartomatous polyps. The family history was negative for both polyposis and cancers. A medical geneticist was called for consultation. Which one of the following genes would most likely NOT be sequenced in this patient to rule out genetic etiologies? A. APC B. BMPR1A C. SMAD4 D. STK11 E. PTEN

A. APC

Histopathological examinations revealed hamartomatous polyps. The family history was negative for both polyposis and cancers. A medical geneticist was called for consultation. Which one of the following gene panels would be the most appropriate first-tier genetic evaluation for this patient? A. APC, MUTYH B. BMPR1A, SMAD4, STK11, PTEN C. MLH1, MSH2, MSH6, PMS2, PSM6 D. MUTYH, STK11, PTEN E. All of the above F. None of the above

B. BMPR1A, SMAD4, STK11, PTEN **SMAD2 corrected to SMAD4

A colonoscopy revealed multiple and diffuse polyps, supporting the diagnosis of FAP. Which one of the following gene-sequencing tests would be the most appropriate first-tier genetic evaluation for this patient? A. APC B. BMPR1A C. MLH1 D. MUTYH E. None of the above

A. APC 5q21

The medical history revealed adenomatous polyposis at the age of 40 and CRC at the age of 56. His family history was unremarkable on both sides. The APC gene was sequenced, and the results were negative. Which one of the following gene-sequencing tests would be the most appropriate next step in the genetic evaluation for this patient? A. BMPR1A B. MLH1 C. MUTYH D. SMAD4 E. PTEN F. None of the above

C. MUTYH MAP is an autosomal recessive adenomatous polyposis syndrome. Individuals with MAP usually have less adenomatous polyposis than patients with familial adenomatous polyposis (FAP), and they have an increased risk of colorectal cancer (CRC). The mean age at onset is about 50 years. Family history is usually negative. Meng, Haiying. Self-assessment Questions for Clinical Molecular Genetics (p. 388). Academic Press. Kindle Edition.

A 10-year-old boy was diagnosed with adenomatous polyposis of the small intestine 2 weeks ago. A colonoscopy detected hundreds of polyposis. Histopathological examinations revealed adenomatous polyps. The family history was negative for both polyposis and cancers. A clinical geneticist was called for consultation. Which one of the following gene panels would be the most appropriate first genetic evaluation for this patient? A. APC, MUTYH B. BMPR1A, SMAD2, STK11, PTEN C. MLH1, MSH2, MSH6, PMS2, PSM6 D. MUTYH, STK11, PTEN E. All of the above F. None of the above

A. APC, MUTYH

How frequently do patients with breast cancer(s) have predisposition mutations in the BRCA1 or BRCA2 gene? A. <1% B. 5%–10% C. 15% D. 20%–25% E. 40%

B. 5%–10%

How frequently do patients with hereditary breast cancer(s) have predisposition mutations in the BRCA1 or BRCA2 gene? A. <1% B. 5%–10% C. 15% D. 20%–25% E. 40%

D. 20%–25% of hereditary BRCA, 5-10% of all BRCA

A 58-year-old Caucasian female was diagnosed with triple-negative multifocal breast cancer. Her medical history was significant for ovarian cancer diagnosed at age 52. Which one of the following genetic tests would be appropriate for this patient? A. BRCA2 sequencing B. BRCA1 sequencing C. BRCA1 and BRCA2 sequencing D. HER2 FISH E. STK11 sequencing F. PTEN sequencing

C. BRCA1 and BRCA2 sequencing 10-20% of TNBC have BRCA1 mutation

A 28-year-old Caucasian female was diagnosed with triple-positive right breast cancer. Which one of the following genetic tests would be appropriate in this patient? A. BRCA2 sequencing B. BRCA1 sequencing C. BRCA1 and BRCA2 sequencing D. HER2 FISH E. HER2 sequencing F. PTEN sequencing

D. HER2 FISH

A biopsy of the breast mass confirmed the diagnosis of triple-negative breast cancer. The family history was positive for a paternal aunt who died of breast cancer and a cousin who was diagnosed with breast cancer at age 36. BRCA1 and BRCA2 tests were ordered for this patient, and the result was negative. Which one of the following genes will NOT be considered in the next step in the workup to rule out genetic etiologies? A. ATM B. CDH1 C. CHEK2 D. PALB2 E. PTEN F. STK11 G. TP53 H. VHL I. All of the above J. None of the above

H. VHL

Prenatal AJ testing. Targeted molecular tests were ordered and pathogenic variants in the BRCA2 gene were detected in both parents. Which one of the following disorders would the couple’s children be at risk of developing besides breast cancer? A. Ataxia telangiectasia B. Bloom syndrome C. Fanconi anemia D. Hereditary telangiectasia E. Nijmegen breakage syndrome F. All of the above G. None of the above

C. Fanconi anemia biallelic BRCA2 mutations

Prenatal AJ testing. Targeted molecular tests were ordered and pathogenic variants in the BRCA2 gene were detected in both parents. If their firstborn child developed Fanconi anemia, which one of the following genes would most likely harbor a pathogenic variant in both parents? A. BRCA1 B. BRCA2 C. PTEN D. TP53 E. VHL

B. BRCA2 The BRCA2 gene is also known as FANCD1.

Preconception counseling. Molecular tests were ordered, and pathogenic variants in the BRCA1 gene were detected in both the husband and the wife. Which one of the following disorders would the couple’s children be at risk of developing besides breast cancer? A. Ataxia telangiectasia B. Bloom syndrome C. Fanconi anemia D. Hereditary telangiectasia E. Nijmegen breakage syndrome

C. Fanconi anemia The BRCA1 gene is also known as FANCS.

52 yo AJ male breast cancer. FHx male BRCA and female OVT. Which one of the following genes should be tested first to rule out genetic etiologies in this patient? A. BRCA1 B. BRCA2 C. CDH1 D. STK11 E. PTEN

B. BRCA2 Male breast cancer is more commonly associated with a BRCA2 mutation than a BRCA1 mutation. And Ashkenazi Jews have a founder mutation in BRCA2, c.5946delT

43 yo patient with genetic counseling. Sister with OVT at 53, mom deceased from BRCA 68, M uncle BRCA and MGF BRCA. Which one of the following individuals in this family should be tested first for a potential genetic etiology? A. Patient B. other family member C. other family member D. Sister E. other family member

D. Sister predictive testing for at risk asymptomatic family members (including children) requires prior identification of the disease-causing variant in the family.

43 yo patient with genetic counseling. Sister with OVT at 53, mom deceased from BRCA 68, M uncle BRCA and MGF BRCA. A. BRCA1 B. BRCA2 C. PTEN D. TP53 E. VHL

B. BRCA2 Male breast cancer is more commonly associated with a BRCA2 mutation than a BRCA1 mutation.

38 yo AJ woman with BRCA. PGM with BRCA at 58 and paternal uncle with PRAD at 45. Which one of the following tests would be the most cost-effective first step in the workup to rule out genetic etiologies in this patient? A. Target mutation analysis of BRCA1 and BRCA2 B. Target mutation analysis of BRCA1 C. Target mutation analysis of BRCA2 D. Sequencing analysis of BRCA1 and BRCA2 E. Sequencing analysis of BRCA1 F. Sequencing analysis of BRCA2

A. Target mutation analysis of BRCA1 and BRCA2 BRCA1 c.68_69delAG (BIC: 185delAG) and c.5266dupC (BIC: 5382insC) and one in BRCA2 c.5946delT (BIC: 6174delT)

Which one of the following mutations in the BRCA1/2 genes would most likely be detected in an AJ patient? A. c.68_69delAG in BRCA1 B. c.68_69delAG in BRCA2 C. c.999del5 in BRCA1 D. c.999del5 in BRCA2 E. All of the above F. None of the above

A. c.68_69delAG in BRCA1 BRCA1 c.68_69delAG (BIC: 185delAG) and c.5266dupC (BIC: 5382insC) and one in BRCA2 c.5946delT (BIC: 6174delT)

Which one of the following mutations in the BRCA1/2 genes would most likely be detected in an AJ patient? A. c.5946delT in BRCA1 B. c.5946delT in BRCA2 C. A large deletion within BRCA1 detected using Southern blot analysis D. A large deletion within BRCA2 detected using Southern blot analysis E. All of the above F. None of the above

B. c.5946delT in BRCA2 BRCA1 c.68_69delAG (BIC: 185delAG) and c.5266dupC (BIC: 5382insC) and one in BRCA2 c.5946delT (BIC: 6174delT)

Which one of the following mutations in the BRCA1/2 genes would most likely be detected in an AJ patient? A. c.5266dupC in BRCA1 B. c.5266dupC in BRCA2 C. c.5966del5 in BRCA1 D. c.5966del5 in BRCA2 E. All of the above F. None of the above

A. c.5266dupC in BRCA1 BRCA1 c.68_69delAG (BIC: 185delAG) and c.5266dupC (BIC: 5382insC) and one in BRCA2 c.5946delT (BIC: 6174delT)

The prevalence of BRCA1 and BRCA2 deleterious mutations is higher in those of Ashkenazi Jewish descent than in those of Western European descent in the United States. Which one of the following genetic terms is most appropriate to describe this phenomenon? A. Founder effect B. Genetic drift C. Genetic heterogeneity D. Incomplete penetrance E. Variable expression

A. Founder effect

As with other hereditary cancer predisposition syndromes, BRCA1 and BRCA2 hereditary breast and ovarian cancer is inherited in an autosomal dominant matter. Individuals carrying a pathogenic variant in BRCA1 or BRCA2 have an increased lifetime risk of developing breast cancer and ovarian cancer. But not everyone with a pathogenic variant in BRCA1 or BRCA2 will develop malignancies in her/his lifetime. Which one of the following genetic terms is most appropriate to describe this phenomenon? A. Founder effect B. Genetic heterogeneity C. Heterozygous advantage D. Incomplete penetrance E. Variable expression

D. Incomplete penetrance

Which one of the following genetic alterations is NOT associated with increased risks for breast cancer? A. BRCA1 B. BRCA2 C. PALB2 D. PTEN E. STK11 F. VHL

F. VHL

A number of models have been developed to assess a woman’s risk of having breast cancer, with varying degrees of validation. Which one of the following situations is suitable for the Gail model? A. An individual with a personal history of breast cancer(s) and/or ovarian cancer(s) B. An individual with a family history of breast cancer(s) and/or ovarian cancer(s) C. An individual without a personal history of breast cancer(s) and limited information on family history D. An individual with personal and family histories of breast cancer(s) and/or ovarian cancer(s) E. An individual or family member(s) with a BRCA1 or BRCA 2 mutation F. None of the above

C. An individual without a personal history of breast cancer(s) and limited information on family history Gail model for women with no history of neoplasia and is a risk assessment tool

A number of models have been developed to assess a woman’s risk of having breast cancer with varying degrees of validation. Which one of the following situations is suitable for the Claus model? A. An individual with a personal history of breast cancer(s) and/or ovarian cancer(s) B. An individual with a family history of breast cancer(s) and/or ovarian cancer(s) C. An individual without a personal history of breast cancer(s) and limited information on family history D. An individual with personal and family histories of breast cancer(s) and/or ovarian cancer(s) E. An individual or family member(s) with a BRCA1 or BRCA2 mutation F. All of the above G. None of the above

B. An individual with a family history of breast cancer(s) and/or ovarian cancer(s) Claus and colleagues developed a risk model for familial risk of breast cancer in a large population-based, case–control study conducted by the Centers for Disease Control and Prevention (CDC). The data were based on 4730 histologically confirmed breast cancer cases in patients 20–54 years of age and on 4688 controls, who were frequency matched to cases on the basis of both geographic region and 5-year categories of age. Family histories with regard to breast cancer in mothers and sisters were obtained through interviews with the cases and controls. The effect of genotype on the risk of breast cancer was shown to be a function of a woman’s age. Carriers of the risk allele were at greater risk at all ages, although the ratio of age-specific risks was greatest at young ages and declined steadily thereafter. The cumulative lifetime risk of breast cancer for women who carried the susceptibility allele was predicted to be high, approximately 92%, while the cumulative lifetime risk for noncarriers was estimated to be 10%. An expansion of the original Claus model estimates breast cancer risk in women with a family history of ovarian cancer. The major drawback of the Claus model is that it does not include any of the nonhereditary risk factors. Another potential drawback of the Claus tables is that they reflect risks for women in the 1980s in the United States. These risks are lower than the current incidence in both North America and most of Europe. As such, an upward adjustment of 3%–4% for lifetime risk is necessary for lifetime risks below 20%. The Gail model focuses primarily on nongenetic risk factors, with limited information on family history. Concordance of the Gail and Claus models has been shown to be relatively poor, with the greatest discrepancies seen with nulliparity, multiple benign breast biopsies, and a strong paternal or first-degree family history. The BRCAPRO model is about BRCA1 and BRCA2 mutation frequencies, cancer penetrance in mutation carriers, cancer status, and age of the consultee’s first-degree and second-degree relatives. The Tyrer–Cuzick model integrates family history, surrogate measures of endogenous estrogen exposure, and benign breast disease in a comprehensive fashion.

A number of models have been developed to assess a woman’s risk of having breast cancer with varying degrees of validation. Which one of the following situations is suitable for the BRCAPRO model? A. An individual with personal history of breast cancer(s) and/or ovarian cancer(s) B. An individual with family history of breast cancer(s) and/or ovarian cancer(s) C. An individual without personal history of breast cancer(s), and limited information on family history D. An individual with personal and family history of breast cancer(s) and/or ovarian cancer(s) E. All of the above F. None of the above

B. An individual with family history of breast cancer(s) and/or ovarian cancer(s) The Gail model focuses on a woman's personal information, including age, family history, and reproductive factors, to estimate the risk of invasive breast cancer. The Claus model, on the other hand, focuses primarily on family history, considering both maternal and paternal lines, and the ages of onset of breast cancer in relatives. Batesuab BRCAPRO is a more comprehensive model that integrates personal and family history to assess the likelihood of carrying a BRCA1 or BRCA2 mutation.

A number of models have been developed to assess a woman’s risk of having breast cancer, with varying degrees of validation. Which one of the following situations is suitable for the use of the Tyrer–Cuzick model? A. An individual with personal history of breast cancer(s) and/or ovarian cancer(s) B. An individual with family history of breast cancer(s) and/or ovarian cancer(s) C. An individual without personal history of breast cancer(s), and limited information on family history D. An individual with personal and family history of breast cancer(s) and/or ovarian cancer(s) E. An individual or family member(s) with a BRCA1 or BRCA 2 mutation F. All of the above G. None of the above

F. All of the above The Tyrer-Cuzick model is generally considered more comprehensive and accurate than the Gail model, particularly for women with a stronger family history of breast cancer. The Tyrer–Cuzick model is based partly on a data set acquired from the International Breast Intervention Study and other epidemiological data. It integrates family history, surrogate measures of endogenous estrogen exposure and benign breast disease in a comprehensive fashion. The major advantage over the Claus model and the BRCAPRO model is that the Tyrer–Cuzick model allows for the presence of multiple genes of differing penetrance. It does produce a readout of BRCA1/2, but also allows for a lower penetrance of BRCAX. The Tyrer–Cuzick model addresses many of the pitfalls of the previous models, significantly, the combination of extensive family history, endogenous estrogen exposure and benign breast disease (atypical hyperplasia).

A 28-year-old female was diagnosed with a bilateral breast cancer. Biopsy results showed that the tumor was estrogen-, progesterone-, and Her2/neu-negative. Which one of the following tests would be most appropriate for this patient to rule out genetic etiologies? A. Sequencing reflex to del/dup analysis of BRCA1 and BRCA2 B. Sequencing reflex to del/dup analysis of PALB2 C. Sequencing reflex to del/dup analysis of STK11 D. Sequencing reflex to del/dup analysis of TP53 E. All of the above F. None of the above

A. Sequencing reflex to del/dup analysis of BRCA1 and BRCA2

A 3-year-old AJ girl was referred to a genetics clinic for a personal history of adrenocortical carcinoma diagnosed at the age of 18 month and rhabdomyosarcoma diagnosed at age 2½. Parents healthy but MFG RCC at 45 and great grandmother osteosarcoma at 44. Which one of the following hereditary cancer predisposition syndromes would this patient most likely have, if she had one? A. Hereditary diffuse gastric cancer B. Li–Fraumeni syndrome C. Lynch syndrome D. PTEN hamartomatous syndrome E. von Hippel–Lindau syndrome

B. Li–Fraumeni syndrome Soft-tissue sarcoma, osteosarcoma, and adrenocortical carcinoma (ACC) are common in individuals with Li–Fraumeni syndrome (LFS).

The physician suspected that the patient had Li–Fraumeni syndrome. Which one of the following assays would most likely be used for the genetic evaluation to confirm the diagnosis in this patient? A. Chromosome breakage study B. Chromosome karyotype C. Chromosome microarray D. Methylation study E. Multicolor flow cytometry FISH (flow-FISH) F. Sequencing G. Targeted-mutation analysis H. None of the above

F. Sequencing

A 3-year-old AJ girl was referred to a genetics clinic for a personal history of adrenocortical carcinoma diagnosed at the age of 18 month and rhabdomyosarcoma diagnosed at age 2½. Parents healthy but MFG RCC at 45 and great grandmother osteosarcoma at 44. Which one of the following genes would most likely be tested to establish the diagnosis? A. CDH1 B. MLH1 C. SMAD4 D. PTEN E. TP53

E. TP53

A 28-year-old female was diagnosed with multifocal breast cancer. Biopsy results showed that the tumor was estrogen-, progesterone-, and Her2/neu-positive. A mastectomy was performed. Her medical history revealed that she had had another surgery to remove rhabdomyosarcomas when she was 5 years old. Which one of the following tests would be most appropriate for this patient to rule out genetic etiologies? A. Sequencing reflex to del/dup analysis of BRCA1 and BRCA2 B. Sequencing reflex to del/dup analysis of PALB2 C. Sequencing reflex to del/dup analysis of STK11 D. Sequencing reflex to del/dup analysis of TP53 E. All of the above F. None of the above

D. Sequencing reflex to del/dup analysis of TP53 . However, childhood cancers are not increased among people with a single mutated BRCA1 or BRCA2 allele.

A 3-year-old girl was diagnosed with rhabdomyosarcoma. Her past medical and family histories were unremarkable. Which one of the following tests would be most appropriate for this patient to rule out genetic etiologies? A. Sequencing reflex to del/dup analysis of RB1 B. Sequencing reflex to del/dup analysis of VHL C. Sequencing reflex to del/dup analysis of WT1 D. Sequencing reflex to del/dup analysis of TP53 E. All of the above F. None of the above

D. Sequencing reflex to del/dup analysis of TP53

An 8-year-old boy was diagnosed with adrenocortical carcinomas (ACC). His past medical and family histories were unremarkable. Which one of the following genetic tests would be most appropriate for this patient to rule out genetic etiologies? A. Sequencing reflex to del/dup analysis of RB1 B. Sequencing reflex to del/dup analysis of VHL C. Sequencing reflex to del/dup analysis of WT1 D. Sequencing reflex to del/dup analysis of TP53 E. All of the above F. None of the above

D. Sequencing reflex to del/dup analysis of TP53 Children with ACC have a 50%–80% chance of having a germline pathogenic variant in the TP53 gene, even in the absence of additional family history.

A 3-year-old girl was diagnosed with choroid plexus tumor. Her past medical and family histories were unremarkable. Which one of the following genetic tests would be most appropriate for this patient to rule out genetic etiologies? A. Sequencing reflex to del/dup analysis of RB1 B. Sequencing reflex to del/dup analysis of VHL C. Sequencing reflex to del/dup analysis of WT1 D. Sequencing reflex to del/dup analysis of TP53 E. All of the above F. None of the above

D. Sequencing reflex to del/dup analysis of TP53

43-year-old female came to a genetics clinic because she was recently diagnosed with breast cancer. Her family history was significant for adrenocortical carcinoma, breast cancer, and osteosarcoma. Which one of the following genetic conditions would most likely be consistent with the clinical presentations in this family? A. Cowden syndrome B. Hereditary breast and ovarian cancer C. Li–Fraumeni syndrome D. Multiple endocrine neoplasia type 1 (MEN1) E. Multiple endocrine neoplasia type 2 (MEN2) F. von Hippel–Lindau

C. Li–Fraumeni syndrome Li–Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome associated with the development of soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias.

43-year-old female came to a genetics clinic because she was recently diagnosed with breast cancer. Her family history was significant for adrenocortical carcinoma, breast cancer, and osteosarcoma. Which one of the following genes should be analyzed first to confirm/rule out genetic etiologies in this family? A. BRCA1 B. BRCA2 C. PTEN D. TP53 E. VHL

D. TP53

A 15-year-old male was diagnosed with pheochromocytoma. History of left kidney resection for multiple focal clear-cell renal-cell carcinomas at age 10. Which one of the following genetic tests would be most appropriate for this patient to rule out genetic etiologies? A. Sequencing reflex to del/dup analysis of RET B. Sequencing reflex to del/dup analysis of SDHB C. Sequencing reflex to del/dup analysis of SDHD D. Sequencing reflex to del/dup analysis of VHL E. None of the above

D. Sequencing reflex to del/dup analysis of VHL hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear-cell renal-cell carcinoma; pheochromocytoma, pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Germline pathogenic variants in the VHL gene on 3p25.3 is the only gene associated with VHL.

A 17-year-old male was diagnosed with multifocal pheochromocytoma. The medical and family history was unremarkable. Which one of the following genetic tests would NOT be appropriate for this patient to rule out genetic etiologies? A. Sequencing reflex to del/dup analysis of RET B. Sequencing reflex to del/dup analysis of SDHB C. Sequencing reflex to del/dup analysis of SDHD D. Sequencing reflex to del/dup analysis of TP53 E. Sequencing reflex to del/dup analysis of VHL

D. Sequencing reflex to del/dup analysis of TP53 Approximately 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma may have an inherited disease caused by a mutation in one of four genes: RET, VHL, SDHD, or SDHB. The recently discovered pheochromocytoma susceptibility genes TMEM127, MAX, and SDHA further expand the differential diagnosis for nonsyndromic paraganglioma and pheochromocytoma. Approximately 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma may have an inherited disease caused by a mutation in one of four genes: RET, VHL, SDHD, or SDHB. The recently discovered pheochromocytoma susceptibility genes TMEM127, MAX, and SDHA further expand the differential diagnosis for nonsyndromic paraganglioma and pheochromocytoma.

Her family history was significant for cerebellar hemangioblastomas, renal-cell carcinoma, and pheochromocytoma. Lily, her older sister, was diagnosed with pheochromocytoma at the age of 43. Lisa, her mother, was diagnosed with renal-cell carcinoma at the age of 46. Her maternal grandfather, Tom, died from cerebellar hemangioblastomas at the age of 56. Which one of the following genetic conditions would most likely be consistent with the clinical presentations in this family? A. Cowden syndrome B. Hereditary breast and ovarian cancer C. Li–Fraumeni syndrome D. Multiple endocrine neoplasia type 1 (MEN1) E. Multiple endocrine neoplasia type 2 (MEN2) F. von Hippel–Lindau

F. von Hippel–Lindau

After consulting a medical geneticist, the physician ordered a next-generation sequencing (NGS) panel for pheochromocytoma. Which one of the following genes would NOT be expected in the NGS panel for this patient? A. NF1 B. RET C. SDHD D. TP53 E. VHL F. None of the above

D. TP53 Approximately 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma may have an inherited disease caused by a mutation in one of four genes: RET, VHL, SDHD, or SDHB. The recently discovered pheochromocytoma susceptibility genes TMEM127, MAX, and SDHA further expand the differential diagnosis for nonsyndromic paraganglioma and pheochromocytoma. Approximately 25% of individuals with pheochromocytoma and no known family history of pheochromocytoma may have an inherited disease caused by a mutation in one of four genes: RET, VHL, SDHD, or SDHB. The recently discovered pheochromocytoma susceptibility genes TMEM127, MAX, and SDHA further expand the differential diagnosis for nonsyndromic paraganglioma and pheochromocytoma.

family history was significant for cerebellar hemangioblastomas, renal-cell carcinoma, and pheochromocytoma (see the pedigree below). Lily, her older sister, was diagnosed with pheochromocytoma at the age of 43. Lisa, her mother, was diagnosed with renal-cell carcinoma at the age of 46. Her maternal grandfather, Tom, died from cerebellar hemangioblastomas at the age of 56. Which one of the following genes should be analyzed first to confirm/rule out genetic etiologies in this family? A. BRCA1 B. BRCA2 C. PTEN D. TP53 E. VHL

E. VHL hemangioblastomas of brain, spinal cord, retina, renal cysts and CCRCC pheochromocytoma, pancreatic cysts, and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts.

38-year-old female came to a genetics clinic because she was recently diagnosed with breast cancer. Her family history was significant for thyroid cancer, breast cancer, and endometrial carcinoma. Which one of the following genetic conditions would most likely be consistent with the clinical presentations in this family? A. Cowden syndrome B. Hereditary breast and ovarian cancer C. Li–Fraumeni syndrome D. Multiple endocrine neoplasia type 1 (MEN1) E. Multiple endocrine neoplasia type 2 (MEN2) F. von Hippel–Lindau disease

A. Cowden syndrome Cowden syndrome, caused by a germline pathogenic variant in PTEN, is a multiple-hamartoma syndrome with an increased risk for benign and malignant tumors of the thyroid, breast, and endometrium.

38-year-old female came to a genetics clinic because she was recently diagnosed with breast cancer. Her family history was significant for thyroid cancer, breast cancer, and endometrial carcinoma. Which one of the following genes should be analyzed first to rule out genetic etiologies in this family? A. BRCA1 B. BRCA2 C. PTEN D. TP53 E. VHL

C. PTEN

A pathogenic variant was detected in the PTEN gene, which was known to cause the PTEN hamartoma tumor syndrome (PHTS). Which one of thyroid cancers would most likely the members of this family have? A. Anaplastic thyroid cancer B. Follicular thyroid cancer C. Medullary thyroid cancer D. Papillary thyroid cancer E. None of the above

B. Follicular thyroid cancer Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules and present by the late 20s. The lifetime risk of developing breast cancer is 85%, with an average age at diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer is approximately 35%. The risk for endometrial cancer may approach 28%. PTEN is the only gene in which pathogenic variants are known to cause PHTS. The most common type of thyroid cancer in individuals with PHTS is follicular, rarely papillary, but never medullary thyroid cancer

A pathogenic variant was detected in the PTEN gene, which was known to cause the PTEN hamartomatous tumor syndrome (PHTS). Which one of thyroid cancers would most likely the members of this family NOT have? A. Anaplastic thyroid cancer B. Follicular thyroid cancer C. Medullary thyroid cancer D. Papillary thyroid cancer E. None of the above

C. Medullary thyroid cancer The PTEN hamartoma tumor syndrome (PHTS), including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome. CS is a multiple-hamartoma syndrome with an increased risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules and present by the late 20s. The lifetime risk of developing breast cancer is 85%, with an average age at diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer is approximately 35%. The risk for endometrial cancer may approach 28%. PTEN is the only gene in which pathogenic variants are known to cause PHTS. The most common type of thyroid cancer in individuals with PHTS is follicular, rarely papillary, but never medullary thyroid cancer

One of the students asks which malignancy is the most common in individuals with Cowden syndrome. Which one of the following would be your answer for this question? A. Breast cancers B. Colorectal cancers C. Endometrial cancers D. Kidney tumors E. Melanomas F. Thyroid cancers

A. Breast cancers 85% in Cowden syndrome, thyroid 35%, endometrial 28%

Gastric cancer FHx but the familial pathogenic variant had not been tested. Which one of the following genetic conditions would be consistent with the clinical presentations in this family? A. Cowden syndrome B. Hereditary diffuse gastric cancer C. Li–Fraumeni syndrome D. Multiple endocrine neoplasia type 1 (MEN1) E. Multiple endocrine neoplasia type 2 (MEN2) F. von Hippel–Lindau

B. Hereditary diffuse gastric cancer

Gastric cancer FHx but the familial pathogenic variant had not been tested. The familial pathogenic variant had not been tested. Which one of the following genes should be tested first to rule out genetic etiologies in this family? A. CDH1 B. MLH1 C. SMAD4 D. PTEN E. TP53

A. CDH1 CDH1 gene account for an estimated 30%–50% of HDGC. cumulative risk for gastric cancer by age 80 years is 67% for men and 83% for women. Women also have a 39%–52% risk for lobular breast cancer

The medical geneticist ordered a sequencing test on the CDH1 gene for this patient, and a pathogenic variant in exon 3 of the gene was detected. Which one of the following malignancies would this patient have an increased risk of developing besides a gastric cancer? A. Breast cancer B. Colorectal cancer C. Endometrial carcinoma D. Osteosarcoma E. Renal-cell carcinoma

A. Breast cancer

Which one of the following populations has higher risk of developing diffuse gastric cancer if they carry a pathogenic variant in the CDH1 gene? A. Male B. Female C. Equal in male and female D. Unknown

B. Female cumulative risk for gastric cancer by age 80 years is 67% for men and 83% for women.

Which one of the following malignancies, in addition to gastric cancer, would a CDH1 patient also have an increased risk of developing in her lifetime? A. Cervical cancer B. Colon cancer C. Lobular breast cancer D. Ovarian cancer E. All of the above F. None of the above

C. Lobular breast cancer Women also have a 39%–52% risk for lobular breast cancer.

What would be the patient’s lifetime risk of developing diffused gastric cancer if she did not undergo elective gastrectomy? A. 20% B. 40% C. 60% D. 80% E. >99%

D. 80% cumulative risk for gastric cancer by age 80 years is 67% for men and 83% for women. The estimated cumulative risk of gastric cancer by age 80 is 80% for both men and women

An 8 yr old boy had chromosome breakage studies were ordered, and the results were positive. Then a Fanconi anemia next-generation sequencing (NGS) panel was ordered. The result showed that the patient had a pathogenic mutation in the FANCB gene. Which one of the following individuals should also be tested for the risk of Fanconi anemia in this family (see the pedigree below)? A. Sister 1 B. Brother C. Sister 2 D. Sister 3 E. All of the above

B. Brother X-linked inheritance Fanconi anemia (FA) is characterized by physical abnormalities, bone-marrow failure, and increased risk of malignancy. Physical abnormalities, such as short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys, and urinary tract; and developmental delay are present in 60%–75% of affected individuals. germline pathogenic variants in FANCB, which are inherited in an X-linked manner.

8 yo boy with chromosome breakage studies were ordered, and the results were positive. Then a Fanconi anemia next-generation sequencing (NGS) panel was ordered, and the result was positive, too. The parents were tested for carrier status. After receiving the parental results, the medical geneticist and the genetic counselor counseled the mother for the increased risk for breast cancer and ovarian cancer. Which one of the following genes is most likely to be mutated in the mother than the others? A. FANCA B. FANCB C. FANCC D. FANCD1 E. FACND2

D. FANCD1 The FANCD1 gene is also called BRCA2. Fanconi anemia may be caused by homozygous or compound heterozygous mutations in the FANCD1/BRCA2. A heterozygous mutation of FANCD1/BRCA2 increases the risk of breast/ovarian cancer in the individual

7 yo girl physical examination revealed that her height was less than 2.5 SD below the mean, and she had two café au lait spots and malformation of her left thumb. A CBC showed leukopenia. Chromosome breakage studies were ordered, and the results were positive. Then a Fanconi anemia next-generation sequencing (NGS) panel was ordered, and the result was positive, too. The parents were tested for carrier status. After receiving the parental results, the medical geneticist and the genetic counselor counseled the mother for the increased risk for breast cancer. Which one of the following genes would most likely be mutated in the mother? A. FANCF B. FANCI C. FANCL D. FANCN E. None of the above

D. FANCN Fanconi anemia (FA) is characterized by physical abnormalities, bone-marrow failure, and increased risk of malignancy. There are at least 15 FA genes identified. A heterozygous mutation of FANCN/PALB2 increases the risk of breast cancer in females

6 yo boy physical examination revealed that his height was less than 2.5 SD below the mean, and he had two café au lait spots and a hypoplastic left thumb. A CBC showed pancytopenia. Chromosome breakage studies were ordered, and the results were positive. Then a Fanconi anemia next-generation sequencing (NGS) panel was ordered, and the result was positive, too. The parents were tested for carrier status. After receiving the parental results, the medical geneticist and the genetic counselor counseled the mother for the increased risk for breast and ovarian cancer. Which one of the following genes would most likely be mutated in the mother? A. FANCE B. FANCG C. FANCI D. FANCJ E. FANCL

D. FANCJ The FANCJ gene is also called BRIP1. Fanconi anemia may be caused by homozygous or compound heterozygous mutations in the FANCJ/BRIP1. A heterozygous mutation of FANCJ/BRIP1 increases the risk of breast cancer in females

A 7-year-old Ashkenazi Jewish girl is brought to a genetics clinic for fatigue and multiple infections, including two pneumonias in 1 month. The physical examination reveals that her height is less than 2.5 SD below the mean, and she has two café au lait spots and absence of the left thumb. A CBC shows pancytopenia. Chromosome breakage studies are positive. A Fanconi anemia next-generation sequencing (NGS) panel is ordered. Which one of the following genes is most likely mutated in this girl? A. FANCA B. FANCB C. FANCC D. FANCG E. FANCN

C. FANCC A single pathogenic variant in complementation group FA-C, the c.456+4A>C in the FANCC gene, is the most common pathogenic variant to FA patients of Ashkenazi Jewish ancestry, and has a carrier frequency of greater than 1/89 in this population. In addition, a mutation (c.65G>A) in FANCA (FA-A is the most common complementation group in non-Jewish patients) and the mutation c.6174delT in FANCD1/BRCA2 are relatively common in the Ashkenazi Jewish population, too, but not as common as the c.456+4A>C in the FANCC gene

Chromosome breakage studies confirmed the diagnosis of Fanconi anemia. A hematopoietic stem-cell transplantation (HSCT) was administrated. For which one of the following conditions would the patient still be at high risk even after HSCT? A. Bone-marrow failure B. Relapse C. Secondary myelodysplastic syndrome (MDS) D. Solid tumor E. All of the above F. None of the above

D. Solid tumor Particularly tongue SCC

Chromosome breakage studies were ordered. The results with a peripheral-blood sample were inconclusive. Which one of the following tests would be most appropriate to establish diagnosis if mosaicism was suspected in this patient? A. Chromosome breakage study with fibroblast cells B. Complementary study C. Diagnose the patient clinically without further tests D. Fanconi anemia next-generation sequencing panel E. None of the above

A. Chromosome breakage study with fibroblast cells diepoxybutane (DEB) or mitomycin C (MMC). It helps in the identification of the abnormal gene of FA but not of mosaicisms. Sensitivity of FA next-generation sequencing panel is 80%–99%, depending on genetic subtypes. -- LARGE dels possibly missed

16 yo with hearing loss and pancytopenia. Chromosome breakage studies confirmed that the patient had Fanconi anemia. Androgen was administrated. The genetic counselor mentioned the increase risk of one disease because of the androgen therapy. For which one of the following disorders would this patient be at increased because of the androgen therapy? A. Infertility B. Liver tumors C. MDS/AML D. Relapse E. All of the above F. None of the above

B. Liver tumors

AJ preconception counseling. The husband’s mother died of bone-marrow failure due to Fanconi anemia (FA). The wife’s family history was uneventful. The physical exanimation was negative. What would be their first child’s risk for FA? A. 1/4 B. 1/8 C. 1/200 D. 1/400 E. 1/800

D. 1/400 Not FANCB if affected female wife 1/89 FANCC (~1/100) husband obligate carrier 1x (1/100) x (1/4) = 400

The physician offered a genetic test for the boy to rule out Fanconi anemia (FA). Which one of the following tests would the physician most likely have ordered for this patient? A. Chromosome breakage study of the peripheral-blood sample B. Complementary study C. Next-generation sequencing of all 15 FA genes D. Target mutation analysis of the FANCC gene E. Target mutation analysis of the FANCA, FANCC, and FANCD1 genes F. None of the above

A. Chromosome breakage study of the peripheral-blood sample a mutation (c.65G>A) in FANCA (FA-A is the most common complementation group in non-Jewish patients) the c.456+4A>C in the FANCC gene, is the most common pathogenic variant in FA patients of Ashkenazi Jewish ancestry; carrier rate 1/89 c.6174delT in FANCD1/BRCA2 are relatively common in the Ashkenazi Jewish population, too,

Chromosome breakage studies were positive. A Fanconi anemia next-generation sequencing (NGS) panel was ordered, and the result was positive, too. Which one of the following sequence changes would most likely be the pathogenic variant detected in this patient? A. p.S849Ffs*40 in FANCA B. c.710-12A>G in FANCA C. p.L717G in FANCB D. p.F713F in FANCB E. c.-490G>T in FANCG F. Not sure

A. p.S849Ffs*40 in FANCA more likely pathogenic than intron, missense, or synonymous

Chromosome breakage studies were ordered, and the results were positive. Then a Fanconi anemia next-generation sequencing (NGS) panel detected a pathogenic variant in the FANCB gene. The mother had been pregnant for 6 weeks (calculated from the first day of her last period), and she asked about the risk of the fetus having the same condition. What would be the unborn child’s risk for Fanconi anemia? A. 1/2 B. 1/4 C. 1/8 D. 1/200 E. 1/400 F. 1/800

B. 1/4 1/2 risk of boy and 1/2 passed on = 1/4

12 yo seizures, gait disturbance, gray hairs and bulbar conjunctival telangiectasias Features. of cerebellar dysfunction such as cerebellar ataxia, dyssynergia, dysarthria, and intentional tremors were present. Deep tendon reflexes were diminished, and plantar responses were flexor. Which one of the following disorders would this patient most likely have if she had a genetic condition? A. Ataxia telangiectasia B. Bloom syndrome C. Fanconi anemia D. Nijmegen breakage syndrome E. All of the above F. None of the above

A. Ataxia telangiectasia Ataxia telangiectasia (AT), Bloom syndrome (BS), Fanconi anemia (FA), and Nijmegen breakage syndrome are so-called chromosomal breakage syndromes. All chromosomal breakage syndromes are autosomal recessive conditions.

The medical geneticist suspected that the patient had ataxia telangiectasia. Which one of the following genes would most likely be mutated in this girl? A. ATM B. BLM C. BRIP1 D. NBN E. None of the above

A. ATM

The ATM gene was sequenced and showed compound heterozygous mutations in the gene. Parental tests confirmed that one was from the father and one from the mother. Which one of the following diseases would the mother have an increased risk of developing in her lifetime? A. Breast cancer B. Cervical cancer C. Endometrial carcinoma D. Insulin-resistant diabetes mellitus E. Leukemia/lymphoma

A. Breast cancer 4x risk kids ALL, lymphoma As individuals with classic AT are living longer, other cancers and tumors, including ovarian cancer, breast cancer, gastric cancer, melanoma, leiomyomas, and sarcomas,

Parents with a child with a clinical diagnosis of ataxia telangiectasia was made. The mother had been pregnant for 6 weeks (calculated from the first day of her last period), and she asked about the risk of the fetus having the same condition. What would be the unborn child’s risk for ataxia telangiectasia? A. 1/2 B. 1/4 C. 1/8 D. 1/12 E. 1/16

B. 1/4 parents obligate carriers so 1/2 x 1/2

The medical geneticist suspected that the patient had Bloom syndrome in a patient with malar photonsensitivity and short stature. Which one of the following assays would most likely be used to diagnose Bloom syndrome in this patient? A. Chromosome breakage study B. Chromosome karyotype C. Methylation study D. Multiplex ligation-dependent probe amplification (MLPA) E. Sister chromatid exchanges F. None of the above

E. Sister chromatid exchanges

Chromosome studies revealed increased sister chromatid exchange. Which one of the following disorders would this patient most likely have? A. Ataxia telangiectasia B. Bloom syndrome C. Fanconi anemia D. Nijmegen breakage syndrome E. All of the above F. None of the above

B. Bloom syndrome

The medical geneticist suspected that the patient had Bloom syndrome. Chromosome studies revealed increased sister chromatid exchange. Which one of the following genes would most likely be mutated in this girl? A. ATM B. BLM C. BRIP1 D. NBN E. None of the above

B. BLM AR dolichocephaly, facial sun-sensitive telangiectatic erythema, patchy areas of hyperpigmentation and hypopigmentation of the skin and moderate to severe immunodeficiency manifested by recurrent respiratory tract and gastrointestinal infections.

Prior Bloom syndrome child. The mother had been pregnant for 6 weeks (calculated from the first day of her last period), and asked about the risk of the fetus having the same condition. What would be the unborn child’s risk of having ataxia telangiectasia? A. 1/2 B. 1/4 C. 1/8 D. 1/12 E. 1/16

B. 1/4 carriers so 1/2x 1/2

AJ patient. The medical geneticist suspected that the patient had Bloom syndrome. Which one of the following assays would be the most cost-effective initial genetic workups to confirm the diagnosis in this patient? A. Chromosome breakage study B. Chromosome karyotype C. Methylation study D. Multiplex ligation-dependent probe amplification (MLPA) E. Sequencing analysis F. Targeted-mutation analysis G. None of the above

F. Targeted-mutation analysis Ashkenazi Jews with Bloom syndrome is c.2207_2212delinsTAGATTC, a 6-bp deletion along with a 7-bp insertion in exon 10 of BLM. This mutation is designated blmAsh. 95%, carrier frequency 1%

An Ashkenazi Jewish couple came to a clinic for preconception counseling. The past medical histories on both sides were unremarkable. The physical examination was negative. The wife’s maternal grandmother died of pulmonary failure due to Bloom syndrome. The family history of the father’s side was negative. What would be their first child’s risk for Bloom syndrome? A. 1/8 B. 1/200 C. 1/400 D. 1/800 E. 1/1000

D. 1/800 wife carrier husband carrier risk 1/100 = 1/2 x (1/100) x (1/4) = 1/800

Bloom syndrome is an inherited disorder characterized by short stature, a skin rash that develops after exposure to the sun, and a greatly increased risk of cancer. It occurs rarely in all national and ethnic groups but is relatively less rare in Ashkenazi Jews. Which one of the following pathogenic variants in the BLM gene is referred as blmAsh because it appears in 1/100 of the Ashkenazi Jewish population? A. 657_661del5 B. c.1089C>A C. c.2407dupT D. c.2207_2212delinsTAGATTC E. All of the above F. None of the above

D. c.2207_2212delinsTAGATTC Ashkenazi Jews with Bloom syndrome is c.2207_2212delinsTAGATTC, a 6-bp deletion along with a 7-bp insertion in exon 10 of BLM. This mutation is designated blmAsh. 95%, carrier frequency 1%

6 yo AJ girl with ID, short stature, bilateral cataracts, SN hearing loss, bilateral basal ganglia calcification. The medical geneticist suspected that the patient had Cockayne syndrome and ordered a genetic test to confirm the diagnosis. Which one of the following assays would the medical geneticist most likely have ordered to confirm the diagnosis in this patient? A. Chromosome breakage study B. Chromosome karyotype C. Methylation study D. Multiplex ligation-dependent probe amplification (MLPA) E. Sequencing analysis F. Targeted-mutation analysis G. None of the above

E. Sequencing analysis Cockayne syndrome is AR ERCC6 (65% of individuals) and ERCC8 (35% of individuals). Most variants can be detected by DNA sequence analysis of the coding and flanking intronic regions of the genes. Deletion/duplication analysis and/or sequencing of the cDNA can detect additional variants in a minority of cases. AJ not a carrier of Cockayne syndrome

The medical geneticist suspected that the patient had Cockayne syndrome and ordered a genetic test to confirm the diagnosis. Which one of the following genes would most likely be included in the molecular genetic test to confirm the diagnosis in this patient? A. ERCC3 B. ERCC4 C. ERCC5 D. ERCC6 E. All of the above F. None of the above

D. ERCC6 Excision Repair Cross-Complementing (ERCC) cachectic dwarfism, cutaneous photosensitivity, loss of adipose tissue, mental retardation, skeletal and neurological abnormalities, and retinopathy. ERCC3, ERCC4, and ERCC5 are associated with autosomal recessive xeroderma pigmentosum.ERCC4 is also associated with autosomal recessive Fanconi anemia.

The medical geneticist suspected that the patient had Cockayne syndrome and ordered a genetic test to confirm the diagnosis. Which one of the following genes would most likely be included in the molecular genetic test to confirm the diagnosis in this patient? A. ERCC1 B. ERCC2 C. ERCC7 D. ERCC8 E. All of the above F. None of the above

D. ERCC8

The medical geneticist suspected that the patient had Cockayne syndrome and ordered a genetic test to confirm the diagnosis. A molecular test was ordered and revealed a pathogenic variant in the ERCC6 gene for Cockayne syndrome. Which one of the following malignancies would the patient have an increased risk of developing in her lifetime? A. Breast cancer B. Cervical cancer C. Colorectal cancer D. Endometrial carcinoma E. Leukemia/lymphoma F. All of the above G. None of the above

G. None of the above Cockayne has no risk of additional malignancies but patients die in the second decade

Which one of the postnatal growth failure disorders is most likely NOT inherited? A. Bloom syndrome B. Cockayne syndrome C. Nijmegen breakage syndrome D. Progeria E. Werner syndrome

D. Progeria LMNA de novo mutation Progeria is also called “Hutchinson–Gilford progeria syndrome” (HGPS). subsequent risk is 1 in 500

The dermatologist suspected that the patient had dyskeratosis congenita and ordered a genetic test for the patient after consulting with a medical geneticist. Which one of the following assays would the dermatologist most likely order to confirm the diagnosis in this patient? A. Chromosome breakage study B. Chromosome karyotype C. Methylation study D. Multiplex ligation-dependent probe amplification (MLPA) E. Sequencing analysis F. Targeted-mutation analysis G. None of the above

E. Sequencing analysis To date, CTC1, DKC1, TERC, TERT, TINF2, NHP2, NOP10, and WRAP53 are the genes in which germline pathogenic variants are known to cause DC and result in very short telomeres. dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. Quantitative measurement of telomere length by flow-FISH is the laboratory test used to aid the diagnosis of dyskeratosis congenita.

The dermatologist suspected that the patient had dyskeratosis congenita, and ordered a genetic test for the patient after consulting a medical geneticist. Which of the following assays would be the most sensitive one to rule out dyskeratosis congenita in this patient? A. Chromosome breakage study B. Chromosome karyotype C. Methylation study D. Multicolor flow cytometry FISH (flow-FISH) E. Sequencing analysis F. Targeted-mutation analysis G. None of the above

D. Multicolor flow cytometry FISH (flow-FISH) Quantitative measurement of telomere length by flow-FISH is the laboratory test used to aid the diagnosis of dyskeratosis congenita

The dermatologist suspected that the patient had dyskeratosis congenita. Which one of the inherited modes does dyskeratosis congenita have? A. Autosomal dominant B. Autosome recessive C. X-linked D. All of the above E. None of the above

D. All of the above DKC1 (Dyskerin 1): X-linked recessive inheritance TERT (Telomerase Reverse Transcriptase): Autosomal dominant or recessive inheritance TERC (Telomerase RNA Component): Autosomal dominant or recessive inheritance TINF2 (Telomere Repeat Binding Factor 2): Autosomal recessive inheritance ACD (Acyl-CoA Dehydratase): Autosomal dominant inheritance CTC1 (Conserved Telomere Protein 1): Autosomal recessive inheritance NHP2 (Non-Homologous End Joining Protein 2): Autosomal recessive inheritance

Mother a carrier and affected boy. Which one of the genes would most likely harbor a pathogenic variant if the patient had dyskeratosis congenita? A. DKC1 B. NHP2 C. TERC D. TERT E. Unknown

A. DKC1 DKC1 gene cause X-linked DC. Pathogenic variants in TERC and TINF2 cause autosomal dominant DC. Pathogenic variants in ACD, RTEL1, and TERT cause autosomal dominant or autosomal recessive DC. Pathogenic variants in CTC1, NHP2, NOP10, PARN, and WRAP53 cause autosomal recessive DC

Which of the following genes would most likely be included in the genetic test to rule out dyskeratosis congenita a patient with AD inheritance pattern? A. DKC1, TERC, and TINF2 B. TERC, TINF2, and TERT C. TERT, NHP2, and NOP10 D. TINF2, TERT, and NHP2

B. TERC, TINF2, and TERT AD = TERT, TERC, ACD, DKC1 (Dyskerin 1): X-linked recessive inheritance TERT (Telomerase Reverse Transcriptase): Autosomal dominant or recessive inheritance TERC (Telomerase RNA Component): Autosomal dominant or recessive inheritance TINF2 (Telomere Repeat Binding Factor 2): Autosomal recessive inheritance ACD (Acyl-CoA Dehydratase): Autosomal dominant inheritance CTC1 (Conserved Telomere Protein 1): Autosomal recessive inheritance NHP2 (Non-Homologous End Joining Protein 2): Autosomal recessive inheritance

The medical geneticist suspected that the patient had Rubinstein–Taybi syndrome (RTS). Which one of the following genetic assays would be the most appropriate initial test for this patient? A. Chromosome breakage study B. Chromosome microarray C. Methylation study D. Multicolor flow cytometry FISH (flow-FISH) E. Sequencing F. None of the above

E. Sequencing 40-50% CREBBP and 3-8% EP300 genes 10% microdeletions FISH

The medical geneticist suspected that the patient had Rubinstein–Taybi syndrome (RTS). In the genetic counseling session, the counselor mentioned that mutations in two genes have been known to cause RTS. How likely would sequencing analyses of both genes detect the pathogenic variant in this patient if he had RTS? A. 20% B. 50% C. 80% D. 99% E. Unknown

B. 50%

A molecular sequencing test was ordered, and the results turned out to be negative. The medical geneticist still suspected RTS in this patient, especially since the detection rate of sequencing analysis of the two genes is only approximately 50%. Which one of the following genetic assays would be most appropriate to further rule out RTS in this patient? A. Chromosome breakage study B. Chromosome karyotype C. Chromosome microarray D. Methylation study E. Multicolor flow cytometry FISH (flow-FISH) F. None of the above

C. Chromosome microarray rule out microdeletions involving CREBBP and/or EP300 in this patient.

Sequencing confirms xeroderma pigmentosum (XP) in a 2yo boy. The mother is pregnant and she wants to find out how likely it will be for her unborn child to have the same condition. What is the estimated recurrent risk of this condition in siblings? A. <1% B. 25% C. 50% D. 50% in brothers

B. 25% Xeroderma pigmentosum (XP) is AR is caused by mutations in at least nine genes, all involved in nucleotide excision repair (NER). These genes are XPA, XPC, DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and POLH.

The dermatologist suspects that the patient has xeroderma pigmentosum (XP), and a sequencing assay confirms the diagnosis. Which one of following cancers will have increased incidence in this XP patient? A. Basal-cell carcinoma B. Gastric carcinoma C. Leukemia D. Lung cancer E. Melanoma F. Squamous-cell carcinoma G. All of the above

G. All of the above 45% SCC or BCC 5% SKCM 10-50X risk for brain, leukemia, lung, gastric tumors

The dermatologist suspects that the patient has xeroderma pigmentosum (XP), and a sequencing assay confirms the diagnosis. Which one of following cancers will most likely develop in this patient with XP? A. Brain cancer B. Gastric carcinoma C. Leukemia D. Lung cancer E. Skin cancer F. All of the above

E. Skin cancer 45% SCC or BCC 5% SKCM

What is expected to be the most characteristic DNA damage after exposure UV light in this patient with XP? A. AA dimer B. TT dimer C. CpG island D. Double strand breakage E. Single strand breakage

B. TT dimer

A 4-year-old boy is referred to a surgeon for an abdominal mass found by ultrasound. He is apparently healthy otherwise. After surgical removal of part of the left kidney, the boy is diagnosed with unilateral and unicentric Wilms tumor. The family history is unremarkable. Molecular genetic tests of the WT1 gene and chromosome microarray analysis are negative. Genetic test for Beckwith–Wiedemann syndrome is negative, too. The parents ask for the estimated recurrent risk for their next child, since the mother is currently pregnant. Which one of the following is the empiric risk of Wilms tumor to the unborn child? A. 50% B. 25% C. 6%–7% D. <1% E. None of the above

D. <1% Nonsyndromic Wilms tumor most frequently occurs as a single occurrence in a family. Empiric risks to the sibs of a proband who represents a simplex case are unknown but likely low (up to 1%) A germline pathogenic variant in the WT1 gene is thought to be the cause of about 10%–15% of Wilms tumors.

The gyral enhancement in right parieto-occipital region was suggestive of angiomatosis. Which one of the following genetic assays would most likely be used for the genetic evaluation to confirm/rule out genetic etiologies in this patient? A. Chromosome karyotype B. Chromosome microarray C. Methylation study D. Multicolor flow cytometry FISH (flow-FISH) E. Sequencing F. Targeted-mutation analysis G. None of the above

B. Chromosome microarray 11p13 deletion of PAX6 (eye and brain) and WT1(Wilms and GU)

A fellow in a clinical molecular genetic laboratory works on a project to develop a next-generation sequencing (NGS) panel for Cowden and Cowden-like syndromes. Which one of the following genes should NOT be included in the panel? A. PTEN B. SDHB C. SDHC D. SDHD E. VHL F. None of the above

E. VHL Cowden-like syndrome may be caused by KLLN promoter hypermethylation, pathogenic variants in SDHB, SDHC, SDHD, or in PIK3CA and AKT1

The pathological examination of a biopsy of the cysts confirmed the diagnosis of pleuropulmonary blastoma. His family history was remarkable for his father having multinodular goiter and a paternal aunt having ovarian Sertoli–Leydig cell tumor. The physician suspected that the patient had a hereditary cancer syndrome. Which one of the following hereditary cancer predisposition syndromes would this patient most likely have? A. DICER1 syndrome B. Gorlin syndrome C. Li–Fraumeni syndrome D. PTEN hamartomatous tumor syndrome E. Xeroderma pigmentosum F. None of the above

A. DICER1 syndrome DICER1 gene, autosomal dominant inheritance which provides instructions for making a protein that is involved in the production of microRNA (miRNA)

18 mo with pleuropulmonary blastoma. Which one of the following genes would most likely be sequenced to rule out genetic etiologies in this patient? A. DICER1 B. ERCC2 C. RET D. PTEN E. TP53 F. None of the above

A. DICER1

Patient with pleuropulmonary blastoma and FHx multinodular goiter and Sertoli-Leydig tumor. Which one of the following genes would be the most appropriate first-line genetic workup to rule out genetic etiologies in this patient? A. DICER1 B. ERCC2 C. RET D. PTEN E. TP53 F. None of the above

A. DICER1

Patient with pleuropulmonary blastoma and bilateral cystic nephroma and FHx multinodular goiter. Which one of the following malignancies would other family members have an increased risk of developing? A. Breast cancer B. Ovarian Sertoli–Leydig cell tumor C. Parathyroid tumor D. Pheochromocytoma E. Renal-cell carcinoma F. None of the above

B. Ovarian Sertoli–Leydig cell tumor Pleuropulmonary blastoma (PPB), cystic nephroma, benign multinodular goiter, and ovarian sex-cord stromal tumors (Sertoli–Leydig cell tumor) Less commonly observed tumors are ciliary body medulloepithelioma (CBME), botryoid-type embryonal rhabdomyosarcoma (ERMS) of the cervix or other sites, nasal chondromesenchymal hamartoma (NCMH), renal sarcoma, pituitary blastoma, and pineoblastoma

Patient with pleuropulmonary blastoma and bilateral cystic nephroma and FHx multinodular goiter and Ovarian Sertoli-Leydig cell tumor. Which one of the following assays would most likely be used for the genetic evaluation of pleuropulmonary blastoma for this patient? A. Chromosome karyotype B. Chromosome microarray C. Methylation study D. Multicolor flow cytometry FISH (flow-FISH) E. Sequencing F. Targeted-mutation analysis G. None of the above

E. Sequencing Sanger

Which one of the following malignancies would most likely be seen in this patient with Gorlin syndrome? A. Breast cancer B. Melanoma C. Basal-cell carcinoma D. Pheochromocytoma E. Renal-cell carcinoma F. None of the above

C. Basal-cell carcinoma

Which one of the following skin cancers is the most common in Caucasians? A. Actinic keratosis B. Basal-cell carcinoma C. Dysplastic nevi D. Melanoma E. Squamous-cell carcinoma F. None of the above

B. Basal-cell carcinoma 2nd is SCC

The results confirmed the patient had Gorlin syndrome. Which one of the following genes would most likely harbor a pathogenic variant in this patient if she had a genetic condition? A. DICER1 B. ERCC2 C. PTCH1 D. PTEN E. TP53 F. VHL

C. PTCH1 nevoid basal-cell carcinoma syndrome” (NBCCS). Approximately 60% of individuals have a recognizable appearance, with macrocephaly, bossing of the forehead, coarse facial features, and facial milia. Other features of Gorlin syndrome include small depressions (pits) in the skin of the palms of the hands and soles of the feet. In people with Gorlin syndrome, the type of cancer diagnosed most often is basal-cell carcinoma. In most individuals, the diagnosis of Gorlin syndrome is established using clinical diagnostic criteria. PTCH1 (formerly PTCH) and SUFU are the only genes in which mutations are known to cause Gorlin syndrome

The results confirmed the patient had Gorlin syndrome. From which one of the following brain tumors did the patient’s maternal uncle most likely die in his childhood? A. Astrocytoma B. Ependymoma C. Glioblastoma D. Medulloblastoma E. Meningioma F. Oligodendroglioma

D. Medulloblastoma 5% of affected individuals with Gorlin syndrome develop medulloblastoma during childhood.

Dyskeratosis congenita with bald tongue, brittle nails, photophobia, epiphora and pancytopenia. Which one of the following genes would most likely be included in the test ordered for the patient? A. DICER1 B. ERCC2 C. FANCA D. PTCH1 E. TERT F. VHL

E. TERT classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. Individuals with DC have an increased risk of developing several life-threatening conditions, such as bone-marrow failure, and pulmonary fibrosis. Approximately half of people with DC have heterozygous mutations in the TERT, TERC, DKC1, or TINF2

Xeroderma pigmentosum with bald tongue, brittle nails, photophobia, epiphora and pancytopenia. Which one of the following assays would be the most sensitive to confirm/rule out genetic etiologies in this patient? A. Chromosome breakage study B. Chromosome microarray C. FISH for gene amplification D. Next-generation sequencing E. Telomere-length measurement F. None of the above

E. Telomere-length measurement

Which one of the following hereditary syndromes is the most commonly seen in children with hepatoblastoma? A. Beckwith–Wiedemann syndrome B. Familial adenomatous polyposis C. Gorlin syndrome D. Li–Fraumeni syndrome E. None of the above

A. Beckwith–Wiedemann syndrome most are sporadic 15% from BWS >> FAP

Histological examinations confirm medullary carcinoma of the thyroid. There is no family history of thyroid cancer. Her mother died of complications of pheochromocytoma after a routine hysterectomy. She has two healthy children, 4 and 8 years old. Which one of the following hereditary cancer predisposition syndromes may be considered to rule out genetic etiologies in this patient? A. Cowden syndrome B. Familial adenomatous polyposis C. Gorlin syndrome D. Multiple endocrine neoplasms, type 1 (MEN1) E. Multiple endocrine neoplasms, type 2 (MEN2) F. All of the above G. None of the above

E. Multiple endocrine neoplasms, type 2 (MEN2)

Medullary carcinoma and FHx of pheochromocytoma. Which one of the following genes may be tested to rule out genetic etiologies? A. DICER1 B. MEN1 C. PTEN D. RET E. TP53 F. VHL

D. RET

Which one of the following thyroid cancers does the patient most likely have if she has multiple endocrine neoplasia type 2 (MEN2)? A. Anaplastic thyroid cancer B. Follicular thyroid cancer C. Medullary thyroid cancer D. Papillary thyroid cancer E. None of the above

C. Medullary thyroid cancer

Mucosal neuromas and pheochromocytoma. Which one of the following hereditary cancer predisposition syndromes would be considered to rule out genetic etiologies in this patient? A. Cowden syndrome B. Familial adenomatous polyposis C. Gorlin syndrome D. Multiple endocrine neoplasms, type 1 (MEN1) E. Multiple endocrine neoplasms, type 2 (MEN2) F. All of the above G. None of the above

E. Multiple endocrine neoplasms, type 2 (MEN2) MEN2B

Mucosal neuromas and pheochromocytoma. Histopathological examinations confirmed the diagnosis of pheochromocytoma. Which one of the following genes may be tested to rule out genetic etiologies in this patient? A. DICER1 B. MEN1 C. PTEN D. RET E. TP53 F. VHL

D. RET

Diagnosis of a well-differentiated neuroendocrine tumor-secreting gastrin. A CT scan of the abdomen identified multiple foci in the pancreas. Later she was again sent to surgery for adhesive intestinal obstruction. Her family history was significant for one of her maternal aunts having a parathyroid tumor. The physician suspected that the patient had a hereditary cancer syndrome. After consulting with a medical geneticist, the physician ordered a molecular test for the patient. Which one of the following hereditary cancer predisposition syndromes might be considered to rule out genetic etiologies in this patient? A. Cowden syndrome B. Familial adenomatous polyposis C. Gorlin syndrome D. Multiple endocrine neoplasms, type 1 (MEN1) E. Multiple endocrine neoplasms, type 2 (MEN2) F. All of the above G. None of the above

D. Multiple endocrine neoplasms, type 1 (MEN1

Patient with pancreatic NET and FHx parathyroid adenoma. Which one of the following genes would most likely be sequenced for this patient to rule out genetic etiologies? A. DICER1 B. MEN1 C. PTEN D. RET E. TP53 F. VHL

B. MEN1

Patient with pancreatic NET and FHx parathyroid adenoma. Which one of the following assays would be most appropriate to confirm/rule out genetic etiologies in this patient? A. Chromosome breakage study B. Chromosome microarray C. Methylation study D. Next-generation sequencing E. Sanger sequencing F. Targeted-mutation analysis G. Telomere-length measurement H. None of the above

E. Sanger sequencing

Which one of the following malignancies is NOT characteristic for multiple endocrine neoplasia syndrome type 1 (MEN1)? A. Adrenocortical tumors B. Carcinoid tumors C. Medullary thyroid cancer D. Pancreatic tumors E. Parathyroid tumors with endocrinopathy F. Pituitary tumors G. All of the above H. None of the above

C. Medullary thyroid cancer

Which one of the following genes is associated with multiple endocrine neoplasia syndrome type 1 (MEN1)? A. BRAF B. KRAS C. MEN1 D. NRAS E. PTEN F. RB1 G. RET H. None of the above

C. MEN1

Which one of the following malignancies is NOT one of characteristics of multiple endocrine neoplasia syndrome type 2 (MEN2)? A. Medullary thyroid cancer B. Mucosal neuroma C. Pheochromocytoma D. Pancreatic tumors E. Parathyroid adenoma F. All of the above G. None of the above

D. Pancreatic tumors

Which one of the following genes is associated with multiple endocrine neoplasia syndrome type 2 (MEN2)? A. BRAF B. KRAS C. MEN1 D. NRAS E. PTEN F. RET G. RB1 H. None of the above

F. RET

Which one of the following genes is associated with familial medullary thyroid carcinomas? A. BRAF B. KRAS C. MEN1 D. NRAS E. PTEN F. RET G. RB1 H. None of the above

F. RET

How often are medullary thyroid carcinomas inherited? A. <1% B. 5% C. 25% D. 50% E. 75%

C. 25%

Which one of the following syndromes is NOT associated with an increased risk for Wilms tumor? A. Beckwith–Wiedemann (BWS) B. Denys–Drash syndrome (DDS) C. Neurofibromatosis type 1 D. Simpson–Golabi–Behmel syndrome (SGBS) E. Trisomy 18 F. WAGR syndrome G. None of the above

C. Neurofibromatosis type I

Developmental delay and café au lait spots. Which one of the following HCPSs might be considered to rule out genetic etiologies in this family? A. Denys–Drash syndrome B. Neurofibromatosis type 1 C. Neurofibromatosis type 2 D. Tuberous sclerosis E. All of the above F. None of the above

B. Neurofibromatosis type 1

Developmental delay and café au lait spots. Which one of the genes would most likely be sequenced to rule out genetic etiologies in this patient? A. NF1 B. NF2 C. TSC1 D. TSC2 E. WT1 F. None of the above

A. NF1

Which one of the following symptoms is NOT likely manifested in individuals with neurofibromatosis type 1 (NF1)? A. Acoustic schwannoma B. Axillary freckling C. Cutaneous neurofibromas D. Lisch nodules E. Malignant peripheral-nerve-sheath tumor F. Optic-pathway tumor

A. Acoustic schwannoma

Bilateral acoustic masses. Which one of the following hereditary cancer predisposition syndromes would be considered to rule out genetic etiologies in this family? A. Denys–Drash syndrome B. Neurofibromatosis type 1 C. Neurofibromatosis type 2 D. Tuberous sclerosis E. All of the above F. None of the above.

C. Neurofibromatosis type 2

Bilateral acoustic masses and facial nerve (CN VII) palsy. Which one of the following genes would most likely be sequenced to rule out genetic etiologies in this family? A. NF1 B. NF2 C. TSC1 D. TSC2 E. WT1 F. None of the above

B. NF2

Bilateral acoustic masses. Which one of the following conditions would most likely cause hearing loss in this patient?A. Astrocytomas B. Ependymoma C. Meningioma D. Neurofibromas E. Schwannoma F. All of the above G. None of the above

E. Schwannoma

Bilateral acoustic masses. Which one of the following assays would most likely be used for the genetic test that the physician ordered for this patient? A. Chromosome breakage study B. Chromosome microarray C. Methylation study D. Next-generation sequencing E. Sanger sequencing F. Targeted-mutation analysis G. Telomere-length measurement H. None of the above

E. Sanger sequencing Sequencing analysis is estimated to identify up to 2/3 of the patients with NF2. Deletion/duplication analysis may detect approximately 20% of patients. So the total sensitivity of sequencing and deletion/duplication is about 90%

The physician suspected that the patient had hereditary pheochromocytoma. After consulting with a medical geneticist, the physician ordered a genetic test for the patient. Which one of the following assays would most likely be used for the genetic test that the physician ordered for this patient? A. Chromosome breakage study B. Chromosome microarray C. Methylation study D. Next-generation sequencing E. Sanger sequencing F. Targeted-mutation analysis G. Telomere-length measurement H. None of the above

D. Next-generation sequencing ten genes play an important role in the pathogenesis of pheochromocytomas: RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, SDH5, and TMEM127. Meng, Haiying. Self-assessment Questions for Clinical Molecular Genetics (p. 423). Academic Press. Kindle Edition.

The physician suspected that the patient had hereditary pheochromocytoma. After consulting with a medical geneticist, the physician ordered a next-generation sequencing (NGS) panel for the patient. Which one of the following genes would most likely be included in the panel for hereditary form of pheochromocytoma to rule out genetic etiologies in this patient? A. BRAF B. KRAS C. MEN1 D. NRAS E. PTEN F. SDHB G. None of the above

F. SDHB

The physician suspected that the patient had hereditary pheochromocytoma. After consulting with a medical geneticist, the physician ordered a next-generation sequencing (NGS) panel for the patient. Which one of the following genes would most likely NOT be included in this panel for the hereditary form of pheochromocytoma to rule out genetic etiologies in this patient? A. MEN1 B. NF1 C. RET D. SDHB E. SDHC F. SDHD G. VHL H. None of the above

A. MEN1

Patient with bilatral intracranial schwannomas. physician suspected that the patient had hereditary pheochromocytoma. After consulting with a medical geneticist, the physician ordered a next-generation sequencing (NGS) panel for the patient. Which one of the following hereditary cancer predisposition syndromes would most likely this patient have if she had one? A. Li–Fraumeni syndrome B. Multiple endocrine neoplasia syndrome, type 1 (MEN1) C. Neurofibromatosis type 1 D. Neurofibromatosis type 2 E. von Hippel–Lindau syndrome F. Cowden syndrome

C. Neurofibromatosis type 1 **book says NF2 so I corrected it

When does retinoblastoma(s) usually occur in an individual? A. Any age B. Before 3 years of age C. Before 5 years of age D. Before 7 years of age E. 12 years of age F. 40 years of age

C. Before 5 years of age

A 2-year-old boy is brought to a clinic for bilateral retinoblastomas (Rb). What is the chance that the patient has a germline pathogenic variant in the RB1 gene? A. >99% B. 80% C. 50% D. 20% E. <1%

A. >99%

After testing, the patient was diagnosed with bilateral retinoblastoma. After consulting with a medical geneticist, the physician ordered a sequencing-based test for the patient. Which one of the following genes would most likely be sequenced to rule out genetic etiologies in this patient? A. GPC3 B. GPC4 C. RB1 D. RET E. WT1 F. None of the above

C. RB1

The physician suspected that the patient had Noonan syndrome. After consulting a medical geneticist, the physician ordered a genetic test for the patient. Which one of the following assays would be most likely be used for the genetic test to rule out Noonan syndrome in this patient? A. Chromosome breakage study B. Chromosome microarray C. Methylation study D. Next-generation sequencing E. Sanger sequencing F. Targeted-mutation analysis G. Telomere-length measurement H. None of the above

D. Next-generation sequencing PTPN11 protein tyrosine phosphatase nonreceptor 11 RAS-MAPK pathway, such as SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1

Which one of the following genes would most likely NOT be sequenced to rule out Noonan syndrome in this patient? A. BRAF B. HRAS C. KRAS D. NRAS E. PTPN11 F. RAF1 G. All of the above H. None of the above

B. HRAS HRAS- Costello syndrome -intellectual disability, distinctive facial appearance, loose folds of skin, and heart problems

Cardiofaciocutaneous syndrome (CFC), Costello syndrome, multiple lentigines syndrome (also called “LEOPARD syndrome”), and Noonan syndrome are clinically overlapping conditions. Which one of the following pathways seems to be involved in the process of the pathogenesis of these syndromes? A. Sonic hedgehog pathway B. PI3K/Akt pathway C. RAS/RAF pathway D. Wnt signal pathway E. All of the above F. None of the above

C. RAS/RAF pathway

Girl and brother with depigmented hair and skin patches. Red fundus and blue irises. The physician suspected that the patient had a genetic condition. Which one of the following hereditary syndromes would the patient most likely have if she had a genetic condition? A. Cardiofaciocutaneous syndrome (CFC) B. Costello syndrome C. Noonan syndrome D. Waardenburg syndrome E. None of the above

D. Waardenburg syndrome neural crest migration PAX3: Responsible for Waardenburg syndrome types 1 and 3 MITF: Responsible for Waardenburg syndrome type 2 SNAI2: Responsible for Waardenburg syndrome type 2 SOX10: Responsible for Waardenburg syndrome type 4 EDN3: Responsible for Waardenburg syndrome type 4 EDNRB: Responsible for Waardenburg syndrome type 4

Waardenburg syndrome. After consulting a medical geneticist, the physician ordered a genetic test for the patient. Which one of the following genes would most likely be included in the genetic test for this patient? A. PAX2 B. PAX3 C. PAX5 D. PXP6 E. All of the above F. None of the above

B. PAX3

A physician suspected that the patient had Waardenburg syndrome. After consulting a medical geneticist, the physician ordered a genetic test for the patient. Which one of the following assays would most likely be used for the genetic test to rule out Waardenburg syndrome in this patient? A. Chromosome breakage study B. Chromosome microarray C. Methylation study D. Next-generation sequencing E. Sanger sequencing F. Targeted-mutation analysis G. Telomere-length measurement H. None of the above

D. Next-generation sequencing

Ambiguous genitalia. An abdominal mass biopsy specimen confirmed the diagnosis of Wilms tumor. Histological evaluations biopsy specimen from the abdominal mass confirmed the diagnosis of Wilms tumor. The patient’s karyotype was 46,XY. The physician suspected that the patient had a genetic condition. Which one of the following hereditary syndromes would the patient most likely have? A. Beckwith–Wiedemann syndrome B. Denys–Drash syndrome C. Frasier syndrome D. Isolated Wilms tumor E. WAGR syndrome F. None of the above

B. Denys–Drash syndrome Frasier syndrome is caused by a germline pathogenic variant in the WT1 gene, too. Frasier syndrome is characterized by focal segmental glomerulosclerosis in early childhood, but no increased risk for Wilms tumor. Males with Frasier syndrome have gonadal dysgenesis. Females with Frasier syndrome usually have normal genitalia. Meng, Haiying. Self-assessment Questions for Clinical Molecular Genetics (p. 427). Academic Press. Kindle Edition.

An abdominal mass biopsy specimen confirmed the diagnosis of Wilms tumor. The patient’s karyotype was 46,XY. The physician suspected that the patient had a genetic condition. After consulting with a medical geneticist, the physician ordered a genetic test for the patient. Which one of the following genes would most likely provide an appropriate molecular diagnosis for this patient? A. ALK B. CDKN1A C. PAX6 D. WT1 E. All of the above F. None of the above

D. WT1 DDS

18 mo with Denys-Drash syndrome (DDS) and diffuse glomerulosclerosis, ambiguous genitalia and Wilms tumor? Which one of the following assays would most likely be used for the genetic test to rule out genetic etiologies in this patient? A. Chromosome breakage study B. Chromosome microarray C. Methylation study D. Next-generation sequencing E. Sanger sequencing F. Targeted-mutation analysis G. Telomere-length measurement H. None of the above

E. Sanger sequencing WT1

The physician suspected that the patient had Costello syndrome. After consulting a medical geneticist, the physician ordered a genetic test for the patient. Which one of the following genes would most likely provide an appropriate molecular diagnosis for this patient? A. BRAF B. HRAS C. KRAS D. NRAS E. PTPN11 F. RAF1 G. All of the above H. None of the above

B. HRAS

The physician suspected that the patient had Costello syndrome. Sequencing of the HRAS gene identified a pathogenic variant in this patient. Which one of the following cancers would this patient have an increased risk of developing in his lifetime? A. Breast cancer B. Colorectal cancer C. Endometrial cancer D. Melanoma E. Neuroblastoma F. Thyroid cancer

E. Neuroblastoma 15% lifetime risk of cancer also rhabdomyosarcoma and urothelial cancer

F. Transitional-cell carcinoma of the bladder

Which one of the following malignancies do patients with Birt–Hogg–Dubé syndrome (BHDS) have an increased risk of developing? A. Breast cancer B. Colorectal cancer C. Endometrial cancer D. Melanoma E. Renal-cell carcinoma F. Thyroid cancer

E. Renal-cell carcinoma hybrid of oncocytoma and chromophobe histologic types FLCN gene- AD inheritance - tumor suppressor

Which one of the following hereditary cancer predisposition syndromes is caused by activating mutations in a proto-oncogene but also can function as a tumor suppressor? A. Birt–Hogg–Dubé syndrome B. Li–Fraumeni syndrome C. Multiple endocrine neoplasia type 1 (MEN1) D. Multiple endocrine neoplasia type 2 (MEN2) E. von Hippel–Lindau syndrome F. All of the above G. None of the above

D. Multiple endocrine neoplasia type 2 (MEN2) *corrected from misprint of MEN1

Which one of the following hereditary cancer predisposition syndromes is caused by activating mutations in a proto-oncogene? A. Birt–Hogg–Dubé syndrome B. Costello syndrome C. Li-Fraumeni syndrome D. Multiple endocrine neoplasia type 1 (MEN1) D. Neurofibromatosis type 1 E. von Hippel–Lindau syndrome F. All of the above G. None of the above

B. Costello syndrome HRAS *MEN1 corrected from MEN2 misprint

What are the four Amsterdan II criteria for Lynch syndrome

1. At least 3 relatives - one first-degree (parent, sibling, child) 2. Two successive generations 3. One relative before age 50 4. Exclude FAP

Oncology consititutional Flashcards

(207 cards)