ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3G>A (p.Met1Ile) (rs80357475)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000584713 SCV000688460 pathogenic Hereditary cancer-predisposing syndrome 2016-03-10 criteria provided, single submitter clinical testing
Invitae RCV000706864 SCV000835938 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-27 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the BRCA1 mRNA. While it is expected to result in an absent or disrupted protein product, alternate in-frame methionines downstream of the initiator codon could potentially rescue the translation initiation. This variant is not present in population databases (ExAC no frequency). While this particular variant has not been reported in the literature, variants affecting the initiator methionine (c.1A>G, c.2T>G, c.2T>C and c.3G>T), have been reported in individuals and families with breast and/or ovarian cancer (PMID: 11595708, 11802209, 12827452, 21120943, 22006311, 24504028), as well as in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 431194). Experimental studies have shown that a different initiator methionine variant (c.2T>G) results in no protein product when expressed in yeast cells (PMID: 21922593). This suggests that disruption of the initiator methionine affects translation initiation and results in loss of BRCA1 protein function. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000706864 SCV000839320 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000989918 SCV001140652 likely pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496941 SCV000586999 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000989918 SCV001242166 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355558 SCV001550479 pathogenic not provided no assertion criteria provided clinical testing The BRCA1 p.Met1? variant was identified in 3 of 59400 proband chromosomes (frequency: 0.00005) from families in a worldwide study by Rebbeck (2018). The variant was also identified in LOVD 3.0 (1x as pathogenic). Please note another variants, c.3G>T and c.3G>C at the same position with different nucleotide change and same amino acid change, p.Met1? were found in ClinVar Database and were classified as pathogenic by multiple submitters. The c.3G>A variant occurs in the first base of the translation initiation site (the methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. The variant was not identified in dbSNP, ClinVar, or UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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