ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5324T>A (p.Met1775Lys) (rs41293463)

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Total submissions: 7
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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) RCV000019265 SCV000244397 pathogenic Breast-ovarian cancer, familial 1 2015-08-10 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 = 1
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019265 SCV000326264 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV001526335 SCV001736649 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-15 criteria provided, single submitter clinical testing This missense variant replaces methionine with lysine at codon 1775 in the BRCT2 domain 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 shown that the mutant protein is highly defective for specific phosphopeptide recognition and transcriptional activity (PMID: 18285836, 20516115). This variant has also been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in two individuals affected with familial breast cancer (PMID: 18285836) and reported to be disease-causing based on multifactorial likelihood analyses (PMID: 18285836, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Met1775Arg, is a well documented pathogenic mutation (Clinvar variation ID: 17694), indicating that methionine at this position is important for BRCA1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
OMIM RCV000019265 SCV000039553 pathogenic Breast-ovarian cancer, familial 1 2008-07-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019265 SCV000053840 likely pathogenic Breast-ovarian cancer, familial 1 2010-06-21 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496817 SCV000587494 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000019265 SCV001243073 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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