Submissions for variant NM_007294.4(BRCA1):c.5324T>A (p.Met1775Lys)

dbSNP: rs41293463

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000019265	SCV000244397	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000019265	SCV000326264	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001526335	SCV001736649	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with lysine at codon 1775 in the BRCT2 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is highly defective for specific phosphopeptide recognition and transcriptional activity (PMID: 18285836, 20516115). This variant has also been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in two individuals affected with familial breast cancer (PMID: 18285836) and reported to be disease-causing based on multifactorial likelihood analyses (PMID: 18285836, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Met1775Arg, is a well documented pathogenic mutation (Clinvar variation ID: 17694), indicating that methionine at this position is important for BRCA1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000019265	SCV002556753	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-06-02	criteria provided, single submitter	clinical testing	The BRCA1 c.5324T>A variant is classified as Pathogenic (PS3, PM2, PM5, PP3, PP5)
Ambry Genetics	RCV001526335	SCV002646820	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-02-24	criteria provided, single submitter	clinical testing	The p.M1775K variant (also known as c.5324T>A), located in coding exon 19 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by lysine, an amino acid with similar properties. This alteration, as well as a known pathogenic close match alteration BRCA2 p.M1775R, were non-functional in many different assays including a colony size assay, a haploid cell survival assay, multiple transcription activation assays, and multiple protein binding and specificity assays (Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32; Drikos I et al. Proteins. 2009 Nov;77:464-76). This alteration was identified in two families in the literature and segregated with disease in both. In one family, this variant was found in cis with BRCA2 p.D1778N, a likely pathogenic splicing alteration (Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic
OMIM	RCV000019265	SCV000039553	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2008-07-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000019265	SCV000053840	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2010-06-21	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496817	SCV000587494	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Brotman Baty Institute, University of Washington	RCV000019265	SCV001243073	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro