CGC Laboratory Genetics & Variant Interpretation 2 — Questions and Answers
Question 1: The American College of Medical Genetics (ACMG) recommends that clinical laboratories report secondary findings in a defined list of genes. These findings are BEST described as:
- Variants found incidentally that are unrelated to the reason for testing but have actionable health implications (Correct answer)
- All variants of uncertain significance found during sequencing
- Variants associated with pharmacogenomics
- Variants that are benign but of scientific interest
Correct answer: Variants found incidentally that are unrelated to the reason for testing but have actionable health implications
ACMG secondary findings are medically actionable variants in a specific gene list found incidentally during sequencing that patients may opt in or out of receiving.
Question 2: Fluorescence in situ hybridization (FISH) is BEST used in clinical genetics to:
- Sequence specific gene regions
- Detect specific chromosomal deletions, duplications, or rearrangements using targeted probes (Correct answer)
- Perform genome-wide copy number analysis
- Identify single-nucleotide variants
Correct answer: Detect specific chromosomal deletions, duplications, or rearrangements using targeted probes
FISH uses fluorescently labeled probes complementary to specific chromosomal regions to detect targeted deletions, duplications, or translocations.
Question 3: The term 'diagnostic yield' in clinical genetics refers to:
- The cost efficiency of a genetic test
- The proportion of tested individuals who receive a molecular diagnosis from a given test (Correct answer)
- The number of variants reported per patient
- The sensitivity of the test for detecting known pathogenic variants
Correct answer: The proportion of tested individuals who receive a molecular diagnosis from a given test
Diagnostic yield is the percentage of patients who receive a definitive molecular diagnosis, which varies by test type, clinical indication, and phenotype.
Question 4: Which of the following is a limitation of whole genome sequencing (WGS) compared to targeted panel testing?
- WGS has lower sensitivity for detecting SNVs
- WGS generates a large number of variants of uncertain significance and incidental findings requiring interpretation (Correct answer)
- WGS cannot detect structural variants
- WGS requires more DNA input than targeted panels
Correct answer: WGS generates a large number of variants of uncertain significance and incidental findings requiring interpretation
The breadth of WGS results in many VUSs and potential secondary/incidental findings that increase interpretive complexity and counseling burden.
Question 5: A laboratory reports a deletion using the term 'copy number variant (CNV).' This means:
- A single nucleotide has been changed
- A segment of DNA has been duplicated or deleted relative to the reference genome (Correct answer)
- A chromosomal translocation has occurred
- Two different genes have been fused
Correct answer: A segment of DNA has been duplicated or deleted relative to the reference genome
CNVs are structural variants involving gains (duplications) or losses (deletions) of genomic segments ranging from kilobases to megabases.
Question 6: When a genetic test result is reported as 'negative,' a genetic counselor should clarify that this means:
- The patient is definitively unaffected and at population risk
- No pathogenic variant was identified in the genes tested, but residual risk may remain (Correct answer)
- The patient cannot be a carrier for the tested condition
- No further testing is warranted under any circumstances
Correct answer: No pathogenic variant was identified in the genes tested, but residual risk may remain
A negative result means no variant was identified in the tested genes, but residual risk exists due to test sensitivity limits and the possibility of variants in untested genes.
CGC Laboratory Genetics & Variant Interpretation 2
The American College of Medical Genetics (ACMG) recommends that clinical laboratories report secondary findings in a defined list of genes.
These findings are BEST described as: