Ace the ABGC Exam: Comprehensive Test Bank for
Domain 3 – Testing, Genomics, & Reproductive Risk!
1. A variant previously classified as "Likely Benign" is re-
evaluated using ACMG’s 2023 Reinterpretation Standards.
Which of the following would most likely upgrade its
classification to "Benign"?
A) Addition of population frequency data from gnomAD
B) Identification of a novel functional study confirming no impact
C) Discovery of the variant in a single affected individual
D) Detection of the variant in a mosaic state
Answer: B
Rationale: Functional studies providing evidence of no impact
align with ACMG’s 2023 guidelines for upgrading variant
classification.
2. A clinical lab identifies a variant with conflicting
computational predictions (some pathogenic, some benign).
According to ACMG/AMP guidelines, how should this be
weighted?
A) Assign strong pathogenic evidence
B) Assign moderate pathogenic evidence
C) Ignore computational predictions
D) Use only consensus tools (e.g., CADD, REVEL)
Answer: D
Rationale: ACMG/AMP guidelines recommend prioritizing
consensus computational tools (e.g., CADD ≥20) over individual
tool discrepancies.
3. Which test limitation is most relevant when comparing SNP
microarray to whole-genome sequencing (WGS)?
A) WGS cannot detect copy-number variants
, B) SNP microarrays may miss variants in GC-rich regions
C) SNP microarrays have higher resolution for small deletions
D) WGS overcalls low-frequency mosaicism
Answer: B
Rationale: SNP microarrays are limited by probe density and may
miss variants in regions with poor probe coverage, such as GC-rich
areas.
4. A patient undergoes exome sequencing. Which action aligns
with ACMG’s Secondary Findings Recommendations Version
3.0?
A) Report all variants in genes with "moderate" actionability
B) Offer return of variants in 69 genes with "strong" evidence
C) Only report incidental findings if requested by the provider
D) Exclude pharmacogenomic results unless specified
Answer: B
Rationale: ACMG v3.0 mandates offering return of variants in 69
genes with "strong" evidence of actionability.
5. A patient on warfarin requires pharmacogenomic testing.
Which guideline directs warfarin dosing based on CYP2C9
and VKORC1 variants?
A) ACMG’s Variant Reinterpretation Standards
B) NSGC’s Carrier Screening Guidelines
C) CPIC Guidelines for Warfarin Dosing
D) AMP’s Somatic Variant Interpretation Framework
Answer: C
Rationale: CPIC provides evidence-based dosing
recommendations tailored to pharmacogenomic variants.
,6. Which testing modality is preferred for detecting structural
variants >100 kb in a pregnancy with ultrasound soft markers?
A) Karyotyping
B) Chromosomal microarray
C) Fetal DNA sequencing
D) Optical genome mapping
Answer: D
Rationale: Optical genome mapping (e.g., OGM) detects large
structural variants missed by microarray or karyotyping.
7. A Jewish patient undergoes carrier screening for Tay-Sachs
disease. Which residual risk calculation method is NSGC 2024
compliant?
A) 1 - (0.5 × carrier frequency)^2
B) 1 - (carrier frequency)^2
C) 1 - (carrier frequency × 0.5)
D) 1 - (carrier frequency × 0.25)
Answer: A
Rationale: Residual risk for Ashkenazi Jewish populations uses 1
- (0.5 × carrier frequency)^2 for autosomal recessive disorders.
8. A blastocyst biopsy result shows mosaic calls for a pathogenic
variant. According to ACMG’s PGT Technical Standards,
which threshold supports a "mosaic" classification?
A) 10-20% variant allele frequency
B) >20% variant allele frequency
C) >50% variant allele frequency
D) <5% variant allele frequency
Answer: B
Rationale: ACMG defines mosaicism as 20-80% variant allele
frequency in blastocyst biopsies.
, 9. Which statement aligns with NSGC’s 2024 Expanded Carrier
Screening Guidelines?
A) Ethnicity-based panels are preferred over universal panels
B) All couples should receive screening for at least 300 conditions
C) Carrier screening should occur preconceptionally only
D) Universal screening for sickle cell disease is recommended for
all populations
Answer: B
Rationale: NSGC 2024 advocates for expanded panels (≥300
conditions) and universal offer regardless of ethnicity.
10. A couple undergoes PGT for a balanced translocation.
Which ACMG standard ensures accurate result
interpretation?
A) Use of single-nucleotide polymorphism (SNP) arrays only
B) Confirmation of mosaic embryos via orthogonal testing
C) Reporting all embryos as "uninformative"
D) Excluding parental karyotype validation
Answer: B
Rationale: ACMG requires orthogonal testing (e.g., FISH or
targeted sequencing) to confirm mosaicism in PGT results.
11. A variant classified as "Likely Pathogenic" under the
2015 ACMG guidelines is re-evaluated in 2023. Which change
in evidence would support reclassification as "Benign" under
the 2023 Reinterpretation Standards?
A) Identification of the variant in a large control cohort
B) Publication of a functional study showing reduced protein
function
C) Discovery of the variant in a patient with the associated
phenotype
D) Updated computational predictions supporting pathogenicity
Answer: A
Domain 3 – Testing, Genomics, & Reproductive Risk!
1. A variant previously classified as "Likely Benign" is re-
evaluated using ACMG’s 2023 Reinterpretation Standards.
Which of the following would most likely upgrade its
classification to "Benign"?
A) Addition of population frequency data from gnomAD
B) Identification of a novel functional study confirming no impact
C) Discovery of the variant in a single affected individual
D) Detection of the variant in a mosaic state
Answer: B
Rationale: Functional studies providing evidence of no impact
align with ACMG’s 2023 guidelines for upgrading variant
classification.
2. A clinical lab identifies a variant with conflicting
computational predictions (some pathogenic, some benign).
According to ACMG/AMP guidelines, how should this be
weighted?
A) Assign strong pathogenic evidence
B) Assign moderate pathogenic evidence
C) Ignore computational predictions
D) Use only consensus tools (e.g., CADD, REVEL)
Answer: D
Rationale: ACMG/AMP guidelines recommend prioritizing
consensus computational tools (e.g., CADD ≥20) over individual
tool discrepancies.
3. Which test limitation is most relevant when comparing SNP
microarray to whole-genome sequencing (WGS)?
A) WGS cannot detect copy-number variants
, B) SNP microarrays may miss variants in GC-rich regions
C) SNP microarrays have higher resolution for small deletions
D) WGS overcalls low-frequency mosaicism
Answer: B
Rationale: SNP microarrays are limited by probe density and may
miss variants in regions with poor probe coverage, such as GC-rich
areas.
4. A patient undergoes exome sequencing. Which action aligns
with ACMG’s Secondary Findings Recommendations Version
3.0?
A) Report all variants in genes with "moderate" actionability
B) Offer return of variants in 69 genes with "strong" evidence
C) Only report incidental findings if requested by the provider
D) Exclude pharmacogenomic results unless specified
Answer: B
Rationale: ACMG v3.0 mandates offering return of variants in 69
genes with "strong" evidence of actionability.
5. A patient on warfarin requires pharmacogenomic testing.
Which guideline directs warfarin dosing based on CYP2C9
and VKORC1 variants?
A) ACMG’s Variant Reinterpretation Standards
B) NSGC’s Carrier Screening Guidelines
C) CPIC Guidelines for Warfarin Dosing
D) AMP’s Somatic Variant Interpretation Framework
Answer: C
Rationale: CPIC provides evidence-based dosing
recommendations tailored to pharmacogenomic variants.
,6. Which testing modality is preferred for detecting structural
variants >100 kb in a pregnancy with ultrasound soft markers?
A) Karyotyping
B) Chromosomal microarray
C) Fetal DNA sequencing
D) Optical genome mapping
Answer: D
Rationale: Optical genome mapping (e.g., OGM) detects large
structural variants missed by microarray or karyotyping.
7. A Jewish patient undergoes carrier screening for Tay-Sachs
disease. Which residual risk calculation method is NSGC 2024
compliant?
A) 1 - (0.5 × carrier frequency)^2
B) 1 - (carrier frequency)^2
C) 1 - (carrier frequency × 0.5)
D) 1 - (carrier frequency × 0.25)
Answer: A
Rationale: Residual risk for Ashkenazi Jewish populations uses 1
- (0.5 × carrier frequency)^2 for autosomal recessive disorders.
8. A blastocyst biopsy result shows mosaic calls for a pathogenic
variant. According to ACMG’s PGT Technical Standards,
which threshold supports a "mosaic" classification?
A) 10-20% variant allele frequency
B) >20% variant allele frequency
C) >50% variant allele frequency
D) <5% variant allele frequency
Answer: B
Rationale: ACMG defines mosaicism as 20-80% variant allele
frequency in blastocyst biopsies.
, 9. Which statement aligns with NSGC’s 2024 Expanded Carrier
Screening Guidelines?
A) Ethnicity-based panels are preferred over universal panels
B) All couples should receive screening for at least 300 conditions
C) Carrier screening should occur preconceptionally only
D) Universal screening for sickle cell disease is recommended for
all populations
Answer: B
Rationale: NSGC 2024 advocates for expanded panels (≥300
conditions) and universal offer regardless of ethnicity.
10. A couple undergoes PGT for a balanced translocation.
Which ACMG standard ensures accurate result
interpretation?
A) Use of single-nucleotide polymorphism (SNP) arrays only
B) Confirmation of mosaic embryos via orthogonal testing
C) Reporting all embryos as "uninformative"
D) Excluding parental karyotype validation
Answer: B
Rationale: ACMG requires orthogonal testing (e.g., FISH or
targeted sequencing) to confirm mosaicism in PGT results.
11. A variant classified as "Likely Pathogenic" under the
2015 ACMG guidelines is re-evaluated in 2023. Which change
in evidence would support reclassification as "Benign" under
the 2023 Reinterpretation Standards?
A) Identification of the variant in a large control cohort
B) Publication of a functional study showing reduced protein
function
C) Discovery of the variant in a patient with the associated
phenotype
D) Updated computational predictions supporting pathogenicity
Answer: A
