Laboratory Genetics & Variant Interpretation Flashcards

According to ACMG/AMP variant classification guidelines, variants are classified into how many categories?

Answer: Five: pathogenic, likely pathogenic, uncertain significance, likely benign, benign

The 2015 ACMG/AMP guidelines established a five-tier classification system: pathogenic, likely pathogenic, VUS, likely benign, and benign.

Which evidence criterion is classified as 'very strong pathogenic' (PVS1) in ACMG/AMP variant interpretation?

Answer: Null variant (nonsense, frameshift, canonical splice site) in a gene where loss of function is a known disease mechanism

PVS1 is assigned to null variants (loss-of-function) in genes where haploinsufficiency or loss-of-function is an established disease mechanism.

Next-generation sequencing (NGS) gene panels in clinical genetics typically involve:

Answer: Targeted sequencing of selected disease-relevant genes

Clinical gene panels use NGS to simultaneously sequence a curated set of genes known to cause a specific disease or disease category.

Chromosomal microarray analysis (CMA) is MOST appropriate as a first-tier test for:

Answer: Individuals with intellectual disability, autism spectrum disorder, or multiple congenital anomalies

CMA is recommended as first-tier testing for unexplained intellectual disability, autism, and multiple congenital anomalies due to its high diagnostic yield (~15–20%).

Whole exome sequencing (WES) sequences:

Answer: All protein-coding exons, approximately 1–2% of the genome

WES captures and sequences the coding exons of all known genes, representing approximately 1–2% of the total genome but containing ~85% of known disease-causing variants.

A mosaic pathogenic variant found in an individual means:

Answer: The pathogenic variant is present in some cells but not all cells of the individual

Mosaicism occurs when a variant arises post-zygotically, resulting in two or more cell populations with different genotypes within the same individual.