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

dbSNP: rs80357061

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048755	SCV000076768	pathogenic	Hereditary breast ovarian cancer syndrome	2024-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1689 of the BRCA1 protein (p.Met1689Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 15172985, 18703817, 25980754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37625). Invitae Evidence Modeling incorporating data from in vitro 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: 15172985, 20516115, 27272900). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000163023	SCV000213511	pathogenic	Hereditary cancer-predisposing syndrome	2025-01-21	criteria provided, single submitter	clinical testing	The c.5066T>G (p.M1689R) alteration is located in exon 16 (coding exon 15) of the BRCA1 gene. This alteration results from a T to G substitution at nucleotide position 5066, causing the methionine (M) at amino acid position 1689 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In one published study, this mutation was shown to segregate with disease in a large 3-generation family (Mirkovic, 2004). This alteration has been classified as likely pathogenic (p>0.9889) by multifactorial analysis (Easton, 2007; Lindor, 2012). This amino acid position is well conserved in available vertebrate species. Functional analysis demonstrated that the p.M1689R alteration lead to a loss-of-function phenotype in both yeast and mammalian transcription assays (Mirkovic, 2004). Another functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031206	SCV000326128	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000048755	SCV000605738	likely pathogenic	Hereditary breast 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 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	2025-04-14	criteria provided, single submitter	clinical testing	Multifactorial studies suggest this variant is associated with breast and ovarian cancer (PMID: 21447777, 21990165, 21990134, 17924331); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5185T>G; This variant is associated with the following publications: (PMID: 24772314, 22086652, 28888541, 28781887, 28277317, 21447777, 21990134, 25980754, 20516115, 17305420, 15235020, 19706752, 26777316, 21990165, 18992264, 27272900, 15172985, 30209399, 29446198, 30765603, 21473589, 17924331, 33087888, 32719484, 35665744, 25348405)
PreventionGenetics, part of Exact Sciences	RCV004554632	SCV004112810	pathogenic	BRCA1-related disorder	2023-04-03	criteria provided, single submitter	clinical testing	The BRCA1 c.5066T>G variant is predicted to result in the amino acid substitution p.Met1689Arg. This variant has been reported many times in individuals with breast cancer (see for examples Abkevich et al. 2004. PubMed ID: 15235020; Easton et al. 2007. PubMed ID: 17924331; Supp. Table 1 in Yurgelun et al. 2015. PubMed ID: 25980754). Functional analyses support the pathogenicity of this amino acid substitution (Lee et al. 2010. PubMed ID: 20516115; Table S4 in Woods et al. 2016. PubMed ID: 28781887). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as Pathogenic/Likely Pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37625/). This variant is interpreted as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001588834	SCV004219437	pathogenic	not provided	2022-11-03	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals and families with breast and/or ovarian cancer (PMIDs: 15172985 (2004), 16267036 (2005), and 18703817 (2008)). Experimental studies have shown that this variant is damaging to transactivation activity, protein folding stability, and phosphopeptide binding activity in both yeast and mammalian structural and functional assays (PMIDs: 14534301 (2003), 17305420 (2007), 18992264 (2009), 20516115 (2010), 21447777 (2011), 27272900 (2016), 28781887 (2016), 30209399 (2018), and 30765603 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001588834	SCV005413224	likely pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	PP5, PM2_moderate, PS3
Sharing Clinical Reports Project (SCRP)	RCV000031206	SCV000053806	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-08-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031206	SCV000145283	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 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, susceptibility to, 1		no assertion provided	in vitro