ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5216A>G (p.Asp1739Gly) (rs80357227)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048867 SCV000076880 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 1739 of the BRCA1 protein (p.Asp1739Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12827452, 9333265, 19491284, 19949876, 15800311) and is reported to segregate with disease in one family (PMID: 15800311). This variant is also known as A5335G in the literature. ClinVar contains an entry for this variant (Variation ID: 55465). Experimental studies have shown that this missense change results in impaired peptide binding activity and specificity, decreased transcriptional activity (PMID: 23867111), reduced protein expression and sensitivity to cisplatin in BRCA1-null mouse embryonic stem cells (PMID: 20516115) and altered colony morphology compared to wild-type protein in yeast (PMID: 15004537). In summary, this is a rare variant that has been observed in several affected individuals, has been reported to co-segregate with disease in a family and has been shown to impact BRCA1 protein function in vitro. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, it has been classified as Likely Pathogenic.
GeneDx RCV000484882 SCV000564750 likely pathogenic not provided 2014-10-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5216A>G at the cDNA level, p.Asp1739Gly (D1739G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant, also known as BRCA1 c.5335A>G by alternative nomenclature, has been observed in multiple individuals with personal and/or family histories consistent with Hereditary Breast and Ovarian Cancer syndrome (Rostagno 2003, Gomez-Garcia 2005, van Harssel 2010). Lee et al (2010) demonstrated that this variant exhibits severely defective folding by a protease sensitivity assay, compromised peptide binding activity, compromised peptide binding specificity and compromised transcriptional activity. Bouwman et al (2013) classified this variant as deleterious based on a cisplatin sensitivity assay. In addition, this variant was demonstrated to disrupt the normal structure of the BRCA1 protein (Mirkovic 2004) and was predicted to be deleterious based on a multifactorial likelihood modeling study (Karchin 2004). BRCA1 Asp1739Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asp1739Gly occurs at a position that is highly conserved across species and is located in between 2 BRCT domains (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 Asp1739Gly to be a likely pathogenic variant.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503925 SCV000591594 uncertain significance not specified 2012-11-16 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112569 SCV000145400 uncertain significance Breast-ovarian cancer, familial 1 1997-11-14 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735457 SCV000863594 uncertain significance Breast and/or ovarian cancer 2012-12-21 no assertion criteria provided clinical testing

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