BRCA1 NM_007294.3:c.5140G>T, Val1714Phe

The p.V1714F variant (also known as c.5140G>T), located in coding exon 16 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5140. The valine at codon 1714 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in 1/141 unrelated individuals diagnosed with breast and/or ovarian cancer (Mannan AU et al. J Hum Genet, 2016 Jun;61:515-22). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

This missense variant replaces valine with phenylalanine at codon 1714 in the BRCT1 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has shown that the variant causes the loss of BRCA1 protein function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with familial breast and ovarian cancer (PMID: 26911350, 29470806, Color internal data) and has been observed to co-segregate with disease (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In addition, a different variant affecting the same codon position (p.Val1714Gly) is considered to be disease-causing (ClinVar variation ID: 55413), suggesting that valine at this position is important for protein structure and function. Based on the available evidence, this variant is classified as Likely Pathogenic.