ClinVar Miner

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

dbSNP: rs80357227
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048867 SCV000076880 likely pathogenic Hereditary breast ovarian cancer syndrome 2022-10-31 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15004537, 20516115, 23867111, 30209399, 32546644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55465). This variant is also known as A5335G. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 12827452, 15800311, 19491284, 19949876). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1739 of the BRCA1 protein (p.Asp1739Gly).
GeneDx RCV000484882 SCV000564750 likely pathogenic not provided 2022-10-11 criteria provided, single submitter clinical testing Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Shattuck-Eidens et al., 1997; Rostagno et al., 2003; Gomez-Garcia et al., 2005; Haffty et al., 2009; van Harssel et al., 2010; Li et al., 2019; Caputo et al., 2021); Published functional studies demonstrate a damaging effect: defective protein folding, compromised peptide binding activity and binding specificity, reduced transcriptional activity, impaired cisplatin sensitivity, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (Lee at al., 2010; Bouwman et al., 2013; Woods et al., 2016; Findlay et al., 2018; Fernandes et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5335A>G; This variant is associated with the following publications: (PMID: 12827452, 20516115, 30209399, 31131967, 15004537, 28781887, 24389207, 23867111, 31447099, 17305420, 15172985, 29752822, 34597585, 19491284, 30765603, 19949876, 15800311, 9333265)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000112569 SCV001434977 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 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.
Color Diagnostics, LLC DBA Color Health RCV001804782 SCV002051822 likely pathogenic Hereditary cancer-predisposing syndrome 2021-04-19 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 1739 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). Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, transcription activation, human haploid cell proliferation and ancillary assays (PMID: 20516115, 30209399. 32546644). This variant has been observed in at least two individuals affected with breast cancer (PMID: 19491284, 33471991; Leiden Open Variation Database DB-ID BRCA1_000426) and several suspected breast and ovarian cancer families (PMID: 9333265, 12827452, 19949876), and it has been reported to cosegregate with disease (PMID: 15800311). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
MGZ Medical Genetics Center RCV000112569 SCV002581474 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-02-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV001804782 SCV002645981 likely pathogenic Hereditary cancer-predisposing syndrome 2021-11-24 criteria provided, single submitter clinical testing The p.D1739G variant (also known as c.5216A>G), located in coding exon 18 of the BRCA1 gene, results from an A to G substitution at nucleotide position 5216. The aspartic acid at codon 1739 is replaced by glycine, an amino acid with similar properties. This alteration has been identified in several cohorts of breast and/or ovarian cancer patients and has been observed to segregate with disease in one of these families (Shattuck-Eidens D et al. JAMA, 1997 Oct;278:1242-50; Rostagno P et al. J. Hum. Genet., 2003 Jun;48:362-6; Gómez-García EB et al. J. Clin. Oncol., 2005 Apr;23:2185-90; Haffty BG et al. Ann. Oncol., 2009 Oct;20:1653-9; van Harssel JJ et al. Fam. Cancer, 2010 Jun;9:193-201; Li JY et al. Int J Cancer, 2019 01;144:281-289). This alteration was also found to be deficient in several functional studies including a high-throughput, genome editing, haploid cell survival assay, a yeast small colony assay, binding activity and specificity assays, transcription activation assays and cisplatin sensitivity assays (Findlay GM et al. Nature, 2018 10;562:217-222; Coyne RS et al. Cancer Biol. Ther., 2004 May;3:453-7; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Bouwman P et al. Cancer Discov, 2013 Oct;3:1142-55; Woods NT et al. NPJ Genom Med, 2016 Mar;1; Bouwman P et al. Clin Cancer Res, 2020 09;26:4559-4568; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69). Several publications predict this alteration to have significant structural impact (Huyton T et al. Mutat. Res., 2000 Aug;460:319-32; , Mirkovic N et al. Cancer Res., 2004 Jun;64:3790-7; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90). 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, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics RCV000112569 SCV004211770 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2021-03-09 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112569 SCV000145400 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 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, susceptibility to, 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000484882 SCV001953415 likely pathogenic not provided no assertion criteria provided clinical testing

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