ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5066T>G (p.Met1689Arg) (rs80357061)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048755 SCV000076768 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 1689 of the BRCA1 protein (p.Met1689Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to co-segregate with disease in a family with several members affected with breast cancer (PMID: 15172985). It has also been seen in unrelated individuals with a history of Lynch syndrome-associated cancer (PMID: 25980754) or breast and/or ovarian cancer (PMID: 18703817). ClinVar contains an entry for this variant (Variation ID: 37625). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 21990134, 17924331). Experimental studies in yeast and human cells have shown that this missense change disrupts the protein folding, BRCT-domain peptide binding, and transcriptional activation activity of the BRCA1 protein (PMID: 20516115, 15172985, 27272900). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000163023 SCV000213511 pathogenic Hereditary cancer-predisposing syndrome 2020-07-13 criteria provided, single submitter clinical testing The p.M1689R pathogenic mutation (also known as c.5066T>G), located in coding exon 15 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5066. The methionine at codon 1689 is replaced by arginine, an amino acid with similar properties. In one published study, this mutation was shown to segregate with disease in a large 3-generation family and was demonstrated to lead to a loss-of-function phenotype in both yeast and mammalian transcription assays (Mirkovic N, et al. Cancer Res. 2004 Jun; 64(11):3790-7). This alteration has been classified as likely pathogenic (p>0.9889) by multifactorial analysis (Easton D et al. Am J Hum Genet. 2007;81:873-883; Lindor NM, et al. Hum. Mutat. 2012 Jan; 33(1):8-21). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031206 SCV000326128 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000048755 SCV000605738 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-03-21 criteria provided, single submitter clinical testing The p.Met1689Arg variant in BRCA1 has been reported in at least 2 individuals wi th BRCA1-associated cancers (Mirkovic 2004, Easton 2007), segregated with diseas e in 3 affected relatives from 1 family (Mirkovic 2004), and was absent from lar ge population studies. In vitro functional studies provide some evidence that th is variant may impact protein function (Lee 2010). However, these types of assay s may not accurately represent biological function. Additionally, computational prediction tools and conservation analysis suggest that the p.Met1689Arg variant may impact the protein, though this information is not predictive enough to det ermine pathogenicity. In summary, although additional studies are required to fu lly establish its clinical significance, this variant is likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048755 SCV000916792 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-17 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5066T>G (p.Met1689Arg) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 277098 control chromosomes (gnomAD). The variant, c.5066T>G, has been reported in the literature in multiple individuals and in at-least one large multigenerational family affected with Hereditary Breast and Ovarian Cancer where it was found to co-segregate with disease (Palma_2008, Mirkovic_2004, Easton_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in multiple independent experimental systems measuring transactivation activity of BRCA1, protease sensitivity to assess protein folding stability, phosphopeptide binding activity, and phosphopeptide binding specificity (Carvalho_2007, Lee_2010, Mirkovic_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001588834 SCV001822616 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Easton 2007, Iversen 2011, Lindor 2012, Valle 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek 2016); Also known as 5185T>G; This variant is associated with the following publications: (PMID: 15235020, 25980754, 28781887, 27272900, 29446198, 15172985, 33087888, 21990134, 20516115, 17305420, 21447777, 32719484, 30209399, 30765603, 17924331, 21990165, 21473589, 22086652, 19706752, 18992264, 24772314, 26777316, 28277317)
Research and Development, ARUP Laboratories RCV001659874 SCV001878411 likely pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031206 SCV000053806 pathogenic Breast-ovarian cancer, familial 1 2012-08-31 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031206 SCV000145283 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048755 SCV000587450 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000031206 SCV001242033 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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