ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5324T>G (p.Met1775Arg) (rs41293463)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131375 SCV000186351 pathogenic Hereditary cancer-predisposing syndrome 2018-03-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA1) RCV000019264 SCV000145453 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131375 SCV000537680 pathogenic Hereditary cancer-predisposing syndrome 2015-10-01 criteria provided, single submitter clinical testing
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
Counsyl RCV000019264 SCV000677661 pathogenic Breast-ovarian cancer, familial 1 2015-07-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000167787 SCV000591612 pathogenic Hereditary breast and ovarian cancer syndrome 2013-05-29 criteria provided, single submitter clinical testing
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
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.
Genologica Medica RCV000019264 SCV000577939 pathogenic Breast-ovarian cancer, familial 1 2017-01-01 criteria provided, single submitter clinical testing
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
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000167787 SCV000076944 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-18 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.
OMIM RCV000019264 SCV000039552 pathogenic Breast-ovarian cancer, familial 1 2006-04-07 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048931 SCV000296388 pathogenic not provided 2015-09-23 criteria provided, single submitter 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
Sharing Clinical Reports Project (SCRP) RCV000019264 SCV000053841 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing

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