ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5140G>T (p.Val1714Phe)

dbSNP: rs1567769244
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000777099 SCV000912785 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-05 criteria provided, single submitter clinical testing 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 (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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). 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.
Ambry Genetics RCV000777099 SCV001185510 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-21 criteria provided, single submitter clinical testing 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. One functional study found the nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay, GM Nature 2018 10;562(7726):217-222) The valine at codon 1714 is replaced by phenylalanine, an amino acid with highly similar properties. 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.
Breast Center,Key Laboratory of Carcinogenesis and Translational Research RCV001254332 SCV001430316 likely pathogenic Hereditary breast ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
GeneDx RCV001759466 SCV001988345 uncertain significance not provided 2020-02-28 criteria provided, single submitter clinical testing Observed in individuals with breast or ovarian cancer (Singh 2018); Published functional studies suggest a damaging effect: classified as non-functional based on results of a cell survival assay (Findlay 2018); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5259G>T; This variant is associated with the following publications: (PMID: 29470806, 30209399)
Brotman Baty Institute,University of Washington RCV001072335 SCV001237696 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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