ClinVar Genomic variation as it relates to human health

The c.8354C>T variant in BRCA2 is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 2785 (p.(Pro2785Leu)). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Reported by three calibrated studies to exhibit protein function similar to benign control variants (PMIDs:38417439, 39779857, 39779848) (BS3 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.008, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. A SpliceAI score of 0.04 predicts no impact on splicing (score threshold <0.10) (BP4 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.15 (based on Family History LR=1.15), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BS3, BP4).

Variant summary: BRCA2 c.8354C>T (p.Pro2785Leu) results in a non-conservative amino acid change located in the OB1 (oligonucleotide binding) fold (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251430 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8354C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2785 of the BRCA2 protein (p.Pro2785Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185253). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.