Submissions for variant NM_007294.4(BRCA1):c.5054C>T (p.Thr1685Ile)

gnomAD frequency: 0.00001  dbSNP: rs80357043

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112476	SCV000244380	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 = 0.999
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112476	SCV000326122	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV001853017	SCV002133120	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 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. ClinVar contains an entry for this variant (Variation ID: 55365). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26689913, 29297111). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1685 of the BRCA1 protein (p.Thr1685Ile). This variant disrupts the p.Thr1685Ala amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17924331, 20516115, 21990134, 27272900). 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.
Ambry Genetics	RCV002336188	SCV002641887	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-28	criteria provided, single submitter	clinical testing	The p.T1685I pathogenic mutation (also known as c.5054C>T), located in coding exon 15 of the BRCA1 gene, results from a C to T substitution at nucleotide position 5054. The threonine at codon 1685 is replaced by isoleucine, an amino acid with similar properties. This alteration has been identified in an individual diagnosed with ovarian cancer (Alhuqail AJ et al. Breast Cancer Res Treat, 2018 Apr;168:695-702). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Multiple functional studies have found this variant to be non-functional including a phosphopeptide binding assay, a specificity assay, a protease sensitivity assay and a haploid cell survival assay (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69; Findlay GM et al. Nature, 2018 10;562:217-222). Another alteration at the same codon, p.T1685A (c.5053A>G), has been identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Additionally, multiple functional studies have found this variant to be non-functional including a phosphopeptide binding assay; a binding specificity assay; a protease sensitivity assay; a homology-directed DNA repair assay, and a haploid cell survival assay (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69; Findlay GM et al. Nature, 2018 10;562:217-222). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112476	SCV000145277	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112476	SCV001237504	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000112476	SCV004243957	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing