Submissions for variant NM_007294.4(BRCA1):c.53T>A (p.Met18Lys)

dbSNP: rs80356929

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Breast Center, Key Laboratory of Carcinogenesis and Translational Research	RCV001254329	SCV001430311	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798249	SCV002043457	likely pathogenic	Breast and/or ovarian cancer	2019-07-16	criteria provided, single submitter	clinical testing
Invitae	RCV001254329	SCV003442385	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-01	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 55559). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met18 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21922593, 21990134, 23161852, 23867111). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 16403807, 18493658, 25823446, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 11748848, 15024741, 32803532). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 18 of the BRCA1 protein (p.Met18Lys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001254329	SCV003933891	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.53T>A (p.Met18Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251084 control chromosomes (gnomAD). c.53T>A has been reported in the literature in multiple individuals, many of Czech ancestry, affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Southey_1999, Machackova_2001, Foretova_2004, Machackova_2019, Wan_2021). These data indicate that the variant is likely associated with disease. Co-occurrences with other pathogenic variants (BRCA2 c.9154C>T , p.Arg3052Trp; BRCA2 c.7007G>A, p.Arg2336His) have also been reported, providing supporting evidence for a benign role; however, in both of these cases there was a history of breast/ovarian cancer on both the paternal and maternal sides of the families (Machackova_2019). Multiple functional studies report experimental evidence evaluating an impact on protein function and found that the variant impairs ubiquitin ligase activity (e.g. Morris_2006, Starita_2015) and showed this variant to have non-functional homology directed repair (HDR) activity (Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Furthermore, a variant affecting the same amino acid (p.Met18Thr) has been classified as pathogenic, suggesting Met18 is important for BRCA1 function. The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 15024741, 11748848, 31409081, 16403807, 10408690, 25823446, 32803532). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111654	SCV000144141	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2005-09-27	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496411	SCV000587003	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000111654	SCV001237744	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro