ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5216A>G (p.Asp1739Gly) (rs80357227)

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Total submissions: 9
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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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000112569 SCV001434977 likely pathogenic Breast-ovarian cancer, familial 1 2018-10-08 criteria provided, single submitter clinical testing The c.5216A>G (p.Asp1739Gly) variant in the BRCA1 gene has been reported in multiple individuals with hereditary breast and ovarian cancer (PMID: 9333265, 12827452, 15800311, 19491284, 19949876). This variant has not been observed in the gnomAD database. Functional assays showed deleterious effect of this change (PMID: 20516115, 23867111). The Asp 1739 is a highly conserved residue, and multiple algorithms predicted this change to be deleterious. Therefore, the c.5216A>G (p.Asp1739Gly) variant in the BRCA1 gene is classified as likley pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112569 SCV000145400 uncertain significance Breast-ovarian cancer, familial 1 1997-11-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000503925 SCV000591594 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asp1739Gly variant was identified in 5 of 3114 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (van Harssel 2010, Rostagno 2003, Haffty 2009, Shattuck-Eidens 1997). The variant was also identified in dbSNP (ID: rs80357227) as "With Likely pathogenic, Pathogenic allele", ClinVar (classified as likely pathogenic by Invitae and GeneDx; as uncertain significance by two submitters), COGR, MutDB, UMD-LSDB (1x as unclassified variant), and in BIC Database (2x with unknown significance). The variant was not identified in Cosmic, ARUP Laboratories, Zhejiang University databases, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Asp1739 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional studies, including in vitro protein folding, phosphopeptide-binding, and cell-based transcriptional assays, predict this variant to be disease associated and classified as deleterious (Karchin 2007, Mirkovic 2004, Lee 2010, Bouwman 2013, Coyne 2004). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
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
Brotman Baty Institute,University of Washington RCV000112569 SCV001241942 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000484882 SCV001740615 likely pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000484882 SCV001953415 likely pathogenic not provided no assertion criteria provided clinical testing

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