ClinVar Genomic variation as it relates to human health

Identified in a high-risk breast cancer family (Byers et al., 2016); Published functional studies demonstrate no impact on splicing (Byers et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8167C>G; This variant is associated with the following publications: (PMID: 12228710, 27273131)

This missense variant replaces leucine with valine at codon 2647 in the DNA binding domain of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported to be functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual affected with breast cancer and in an unaffected individual (PMID: 27273131, 33471991; Leiden Open Variation Database DB-ID BRCA2_003789). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same amino acid position, p.Leu2647Pro, is considered to be disease-causing (ClinVar variation ID: 52443), suggesting that leucine at this position is important for BRCA2 function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.L2647V variant (also known as c.7939C>G), located in coding exon 16 of the BRCA2 gene, results from a C to G substitution at nucleotide position 7939. The leucine at codon 2647 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in a woman with a personal history of early onset breast cancer (Byers H et al. Eur. J. Hum. Genet., 2016 11;24:1591-1597). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: BRCA2 c.7939C>G (p.Leu2647Val) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 1461876 control chromosomes (gnomAD database v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.7939C>G has been reported in the literature in at-least one individual affected with female breast cancer and authors classified the variant as VUS (example: Byers_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27273131). ClinVar contains an entry for this variant (Variation ID: 186112). Based on the evidence outlined above, the variant was classified as uncertain significance.