Genomic Testing & Interpretation Flashcards

Which of the following is NOT a standard ACMG/AMP variant classification category?

Answer: Likely deleterious

The five ACMG/AMP tiers are pathogenic, likely pathogenic, VUS, likely benign, and benign.

The ACMG/AMP criterion PVS1 applies to which type of variant?

Answer: A null variant in a gene where loss of function is a known disease mechanism

PVS1 is very strong evidence for nonsense, frameshift, canonical splice-site, or similar null variants in LOF-mechanism genes.

A variant has an allele frequency of 8% in a large general population database. Which ACMG/AMP criterion is most applicable?

Answer: BA1, a stand-alone benign criterion

An allele frequency above 5% is considered stand-alone evidence for a benign classification.

A missense variant is confirmed de novo in a child with a consistent phenotype, with maternity and paternity confirmed. What ACMG/AMP evidence does this support?

Answer: PS2, a strong pathogenic criterion

A confirmed de novo variant with a matching phenotype supports pathogenicity, with PS2 requiring confirmed parentage.

A laboratory reclassifies a previously reported VUS as likely pathogenic. What is the most appropriate next step?

Answer: Issue an amended report to the ordering provider so the patient can be recontacted

Reclassifications that affect care should be communicated through an amended report so the provider can recontact the patient.

An unaffected relative is being considered for predictive testing based on a family member's VUS. What is the correct approach?

Answer: Do not use the VUS for clinical decisions; manage by personal and family history

A VUS should not drive clinical management or cascade testing, and care should follow history-based risk.

Under the ClinGen SVI recommendations, how is the PM2 criterion (absent or extremely rare in population databases) now generally applied?

Answer: At supporting strength

ClinGen SVI recommended downgrading PM2 from moderate to supporting strength.