Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Consortium of Investigators of Modifiers of BRCA1/2 |
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. |
| Invitae | RCV001387017 | SCV001587504 | pathogenic | Hereditary breast ovarian cancer syndrome | 2021-12-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects BRCA1 function (PMID: 21922593, 30209399). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 54745). 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). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BRCA1 mRNA. The next in-frame methionine is located at codon 18. |
| Breast Cancer Information Core |
RCV000111545 | SCV000144006 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2002-05-29 | no assertion criteria provided | clinical testing | |
| Brotman Baty Institute, |
RCV000111545 | SCV001242164 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |