ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5144G>A (p.Ser1715Asn)

dbSNP: rs45444999
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112507 SCV001161553 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.999494
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508636 SCV000605905 likely pathogenic not provided 2017-01-27 criteria provided, single submitter clinical testing
Counsyl RCV000112507 SCV000785557 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-09-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023609 SCV001185514 pathogenic Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing The p.S1715N pathogenic mutation (also known as c.5144G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5144. The serine at codon 1715 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. This alteration was found to segregate with both breast and ovarian cancer in multiple individuals from a large British family (Campbell J et al. Clin. Genet., 2013 May;83:485-7) and has been identified in a family with multiple cases of breast cancer from a cohort of 83 Spanish breast and/or ovarian cancer families (Díez O et al. Int. J. Cancer, 1999 Nov;83:465-9). Numerous functional studies have shown that this variant is functionally defective including in homology directed repair, haploid cell survival, yeast growth retardation, transcriptional activation assays, binding activity and specificity, protease sensitivity, and overall stability (Vallon-Christersson J et al. Hum. Mol. Genet., 2001 Feb;10:353-60; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem., 2010 Jun;285:20080-7; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88; Findlay GM et al. Nature, 2018 10;562:217-222). This variant was determined to be pathogenic in a multifactorial analysis which combined family history, pathology, and co-segregation data (Parsons M. et al. Hum. Mutat. 2019 09;40(9):1557-1578). Internal structural analysis determined that this variant is highly destabilizing to the local structure (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV001023609 SCV001343897 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing This missense variant replaces serine with asparagine at codon 1715 in BRCT domain of the BRCA1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies reported this variant to be abnormal in a haploid cell proliferation assay (PMID: 30209399) and showed reduced activities in transcriptional activation, protein stability, peptide binding, subcellular localization and homology-directed DNA repair assays (PMID: 11157798, 20378548, 20516115, 30257991). Additionally, this variant has been analyzed by multifactorial analysis and classified as Pathogenic (PMID: 31131967). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 22856468, 12955719, 12955716). It has been shown that this variant segregates with disease (PMID: 22856468). 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.
Invitae RCV001853019 SCV002139227 pathogenic Hereditary breast ovarian cancer syndrome 2021-12-03 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1715 of the BRCA1 protein (p.Ser1715Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10508480, 22856468). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55416). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11157798, 20516115, 28781887, 30209399, 30765603). This variant disrupts the p.Ser1715 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11157798, 20516115, 29176636). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112507 SCV000145329 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112507 SCV001241766 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000508636 SCV001553242 uncertain significance not provided no assertion criteria provided clinical testing

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