👉There are publicly available algorithms for whittling down these variant lists, but we are often left with a handful that cannot be definitively classified as benign or pathologic.
👉These are the variants of uncertain clinical significance (VUS).
👉There is a 20% to 40% chance that a modern multigene panel test will identify a VUS, compared with only a 5% chance that it will identify a clinically useful pathologic mutation in a gene that is not BRCA1 or BRCA2.
👉This is a temporary situation, however, as VUS rates will decline as more is learned about these genes.
👉Patients can help advance knowledge in this area by participating in the Prospective Registry Of MultiPlex Testing (PROMPT), which is curating family history and genetic test results with the goal of facilitating reclassification of VUS cases (http://promptstudy.info/).
👉Most VUS are missense mutations; that is, a single nucleotide has changed, leading to a different amino acid in the final protein.
👉This might appear in the report as something such as Gene X c.78G>C p.Trp26Cys, which means that in the cDNA (c.), the 78th nucleotide has changed from glycine to cytosine, resulting in the 26th amino acid of the protein (p.) changing from a tryptophan to a cysteine.
👉Most (but not all) missense VUS are eventually reclassified as benign.
👉Pathologic mutations are mostly of the truncating type.
👉That is, there is a deletion or insertion of one or two nucleotides (or some other number that is not a multiple of three) leading to a shift in the reading frame that often results in early termination of transcription, producing a short, dysfunctional protein.
👉These appear in the report as something such as Gene Xc.291delT p.Arg97Glyfs*26, which means that a thymine, which was the 291st nucleotide in the cDNA (c.), has been lost, resulting in the 97th amino acid in the protein (p.) changing from an arginine to a glycine while shifting the reading frame (fs), leading to a stop codon (*) 26 amino acids later.
👉Other pathologic mutations include deletion or rearrangement of large segments of the gene. This also leads to a very altered, dysfunctional protein.
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