ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5324T>G (p.Met1775Arg) (rs41293463)

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Total submissions: 19
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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) RCV000019264 SCV000244398 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
Invitae RCV000167787 SCV000076944 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 1775 of the BRCA1 protein (p.Met1775Arg). 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 segregate with breast cancer in a single family (PMID: 7545954), and has also been observed in several unrelated individuals affected with breast cancer (PMID: 22144684, 7939630). ClinVar contains an entry for this variant (Variation ID: 17694). Experimental studies have shown that this missense change reduces protein stability (PMID: 23161852, 14534301), and disrupts protein-protein binding and transcriptional transactivation (PMID: 20516115, 12400015, 19493677). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131375 SCV000186351 pathogenic Hereditary cancer-predisposing syndrome 2020-01-04 criteria provided, single submitter clinical testing The p.M1775R pathogenic mutation (also known as c.5324T>G), located in coding exon 19 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by arginine, an amino acid with similar properties. This alteration is located in the highly conserved BRCT repeat domain of BRCA1 and has been shown to have a severe impact on normal BRCA1 function/activity (Carvalho M et al. Cancer Res. 2007 Feb;67:1494-501; Nikolopoulos G et al. Biochim. Biophys. Acta. 2007 Jun;1774:772-80). Of note, this alteration is also designated as 5443T>G in published literature. This alteration has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee M et al. Hum. Mutat. 2012 Jan;33:22-8). Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx RCV000048931 SCV000210213 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5324T>G at the cDNA level, p.Met1775Arg (M1775R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). Using alternate nomenclature, this variant would be defined as BRCA1 5443T>G. BRCA1 Met1775Arg has been well established as a pathogenic variant which abolishes BRCA1 activity, including double strand break repair, transcription, and binding functions (Monteiro 1996, Williams 2003, Varma 2005, Tischkowitz 2008). This variant has been observed in association with hereditary breast and ovarian cancer and has been reported as a recurrent variant in the African population (Futreal 1994, Miki 1994, Zhang 2012, Donenberg 2016). BRCA1 Met1775Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the BRCT2 domain and in a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Another non-conservative variant at the same residue, Met1775Lys, is also classified as pathogenic (Monteiro 1996). Based on currently available evidence, we consider BRCA1 Met1775Arg to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048931 SCV000296388 pathogenic not provided 2019-11-27 criteria provided, single submitter clinical testing Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Strong co-segregation with disease in affected individuals from a single family.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019264 SCV000326265 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131375 SCV000537680 pathogenic Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing
Genologica Medica RCV000019264 SCV000577939 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
Counsyl RCV000019264 SCV000677661 pathogenic Breast-ovarian cancer, familial 1 2015-07-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167787 SCV000699236 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-20 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5324T>G (p.Met1775Arg) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic Methionine (M) with a large size and basic Arginine (R) located in the BRCT domain. Consistently, 5/5 in silico tools predict a damaging outcome for this variant. The variant is absent in 124492 control chromosomes while it was reported in several HBOC patients including one family in which it was shown to co-segregate with the disease, indicating its pathogenicity. Moreover, functional studies demonstrated the variant to impair homology directed repair, single strand annealing, phosphopeptide-binding and transcriptional activity of BRCA1 further supporting a deleterious impact. Additionally, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170589 SCV001333177 pathogenic Breast and/or ovarian cancer 2017-11-06 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001659723 SCV001878764 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
OMIM RCV000019264 SCV000039552 pathogenic Breast-ovarian cancer, familial 1 2006-04-07 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019264 SCV000053841 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019264 SCV000145453 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 RCV000167787 SCV000587495 pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048931 SCV000591612 pathogenic not provided no assertion criteria provided clinical testing The p.Met1775Arg variant was identified in the UMD 2X as a causal variant, in BIC 31X as a variant of unknown clinical importance, and also in the HGMD and LOVD databases. The variant was identified in dbSNP (ID#rs41293463) as a clinically associated SNP, with no population frequency data. In addition, this variant was not identified in 1000 control chromosomes from healthy individuals from one study (Phelan 2005), and was not reported in the Exome Variant Server ESP Project. This variant has been found to segregate with disease in one kindred (Miki 1994). The p.Met1775 residue is conserved across mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Met1775Arg variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Several functional studies have concluded that this variant has a deleterious effect on BRCA1 protein function. The mutation has been shown to inhibit the interaction of BRCA1 with the DNA helicase BACH1 (Clapperton 2004, Shiozaki 2004) and with the transcriptional corepressor CtIP (Varma 2005), and yeast and mammalian cell-based assays have demonstrated that the variant impairs transcription activation (Monteiro 1996, Phelan 2005, Tischkowitz 2008). One study utilized a proteolytic sensitivity assay which indicated that the variant results in a folding defect in the BRCT domains, and thus destabilization of this domain (Williams 2003). The authors of this study suggest that this abrogates BRCA1 function, and may explain the spectrum of defects observed in other studies. In summary, based on the above information, this variant is classified as pathogenic.
Hereditary Cancer Genetics group,Vall d'Hebron Institute of Oncology RCV000167787 SCV000916357 pathogenic Hereditary breast and ovarian cancer syndrome 2019-03-01 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000019264 SCV001238126 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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