ClinVar Miner

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

dbSNP: rs45444999
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Total submissions: 10
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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 Diagnostics, LLC DBA Color Health RCV001023609 SCV001343897 pathogenic Hereditary cancer-predisposing syndrome 2023-05-10 criteria provided, single submitter clinical testing This missense variant replaces serine with asparagine at codon 1715 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in a haploid cell proliferation assay, transcription activation assays, homology-directed DNA repair assay, a nuclear localization assay, and other ancillary assays (PMID: 11157798, 20516115, 29884841, 30209399, 30257991). This variant has been reported in affected members of two hereditary breast and ovarian cancer families (PMID: 12955716, 12955719, 22856468) and reported in additional suspected hereditary breast and ovarian cancer families (PMID: 34597585). This variant is reported to segregate with breast and/or ovarian cancer (PMID: 12955716, 12955719, 22856468), and two multifactorial analysis have reported likelihood ratios for pathogenicity based on segregation of 57.86 and 167.97 (PMID: 31131967, 34597585). 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 Pathogenic.
Invitae RCV001853019 SCV002139227 pathogenic Hereditary breast ovarian cancer syndrome 2023-11-27 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 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 with a positive predictive value of 95%. 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.
GeneDx RCV000508636 SCV002577234 pathogenic not provided 2022-03-31 criteria provided, single submitter clinical testing Observed in individuals with breast and/or ovarian cancer, and segregates with disease in one large family (Dez 1999, Campbell and Speevak 2013); Published functional studies demonstrate a damaging effect: impaired transciptional activity, structural stability, binding activity and specificity, protease sensitivity, cell survival, and homology-directed repair activity (Vallon-Christersson 2001, Lee 2010, Woods 2016, Findlay 2018, Fernandes 2019, Petitalot 2019, Lyra 2021); Multifactorial likelihood analyses suggest this variant is pathogenic (Parsons 2019, Caputo 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 5263G>A; This variant is associated with the following publications: (PMID: 17305420, 11157798, 25782689, 30209399, 30765603, 20516115, 33087888, 28781887, 31131967, 30257991, 10508480, 34597585, 21447777, 22856468)
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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