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

dbSNP: rs80357111

Total submissions: 6

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, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000111545	SCV000785479	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001017950	SCV001179120	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-09	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the BRCA1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 05;39(5):593-620). 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 Oct;8(10): 833-7; Brzovic PS et al. J. Biol. Chem. 2001 Nov;276(44):41399-406; Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10):5646-51). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387017	SCV001587504	pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-05	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the BRCA1 mRNA. The next in-frame methionine is located at codon 18. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon 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). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects BRCA1 function (PMID: 21922593, 30209399). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111545	SCV000144006	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111545	SCV001242164	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro