Submissions for variant NM_007294.4(BRCA1):c.5365G>T (p.Ala1789Ser)

dbSNP: rs80357078

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580957	SCV000683306	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1789 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 reported that this variant does no impact BRCA1 function in protein stability, phosphopeptide binding and specificity, transcription activation and homology-directed repair assays (PMID: 20516115, 28781887, 30257991) and in a haploid cell proliferation assay (PMID: 30209399) This variant has been reported in an individual affected with early-onset breast cancer with no family history of disease (PMID: 15887246). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.5365G>A (p.Ala1789Thr), has been identified in individuals affected by breast and/or ovarian cancer (PMID: 18680205, 20737206, 30264118, 30287823, Color internal data) and has been reported to impair BRCA1 protein function in several functional studies (PMID: 18680205, 19493677, 20737206, 28781887, 29884841, 30209399, 32546644), suggesting that Ala at this position is important for the protein function. However, the same functional assays, that reported the p.Ala1789Thr variant to be defected, found our variant in question, p.Ala1789Ser, has no impact on BRCA1 function (PMID: 29884841, 30209399). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112629	SCV000744585	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000112629	SCV000785154	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-09	criteria provided, single submitter	clinical testing
Invitae	RCV001853023	SCV002313770	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1789 of the BRCA1 protein (p.Ala1789Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 15887246). ClinVar contains an entry for this variant (Variation ID: 55553). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 20516115, 30257991, 30765603). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001689610	SCV002550942	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580957	SCV002645113	likely benign	Hereditary cancer-predisposing syndrome	2021-04-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112629	SCV000145483	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112629	SCV001243176	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001689610	SCV001906387	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001689610	SCV001953263	benign	not specified		no assertion criteria provided	clinical testing