ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5207T>G (p.Val1736Gly) (rs45553935)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000585937 SCV000699221 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5207T>G (p.Val1736Gly) results in a non-conservative amino acid change located in the BRCT domain 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 277208 control chromosomes. c.5207T>G has been reported in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, internal data). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A functional study demonstrated the variant to decrease protein stability, phosphopeptide binding activity, phosphopeptide binding specificity and transcriptional activity of BRCA1 (Lee_2010). Multiple studies involving computational analysis predict this variant to be pathogenic/deleterious (Cao_2019, Thompson_2016, Woods_2016, Karchin_2007, Pavlicek_2004). Different variants at the same codon such as c.5207delT, c.5207T>C are listed in databases (ClinVar, HGMD) with disease causing outcome indicating the variant to be located in a mutational hotspot and the clinical relevance of the Val1736 residue. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV001023725 SCV001185640 pathogenic Hereditary cancer-predisposing syndrome 2019-11-27 criteria provided, single submitter clinical testing The p.V1736G pathogenic mutation (also known as c.5207T>G), located in coding exon 18 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5207. The valine at codon 1736 is replaced by glycine, an amino acid with dissimilar properties. A transcription activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J. Biol. Chem., 2019 04;294:5980-5992). Additionally, a functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222) and another functional study found this alteration to be severely defective in all assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV001023725 SCV001343891 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112563 SCV000145393 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112563 SCV001242412 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
King Laboratory,University of Washington RCV001171388 SCV001251286 benign not specified 2019-09-01 no assertion criteria provided research

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