ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2T>C (p.Met1Thr) (rs80357111)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111545 SCV000325520 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000111545 SCV000785479 likely pathogenic Breast-ovarian cancer, familial 1 2017-08-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV001017950 SCV001179120 pathogenic Hereditary cancer-predisposing syndrome 2018-04-12 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.2T>C), located in coding exon 1 of the BRCA1 gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. Pathogenic mutations affecting the initiation codon in BRCA1, such as c.1A>G, has been reported in a number of breast and ovarian cancer families (Meindl A et al. Int J Cancer. 2002;97(4):472-80; Walsh T et al. Proc Natl Acad Sci U S A. 2011;108(44):18032-7; Norquist B et al. J. Clin. Oncol. 2011;29(22):3008-15; Cunningham JM et al. Sci Rep 2014;4:4026). This alteration is predicted to result in the loss of the first 17 amino acids of BRCA1. These RING domain residues comprise a significant portion of the N-helix of the four helix bundle that is crucial for BARD1/BRCA1 dimerization which, in turn, is responsible for their mutual stability, appropriate nuclear localization, and ubiquitin ligase activity (Brzovic PS et al. Nat Struct Biol. 2001;8(10): 833-7; Brzovic PS et al. J Biol Chem. 2001;276(44):41399-406; Brzovic PS et al. PNAS. 2003;100(10):5646-51). Sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001387017 SCV001587504 pathogenic Hereditary breast and ovarian cancer syndrome 2020-02-05 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). This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 54745). 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. This variant disrupts the p.Met1 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22006311, 9145677, 11595708, 11802209, 12827452, 21120943, 24504028). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111545 SCV000144006 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000111545 SCV001242164 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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