Submissions for variant NM_007294.4(BRCA1):c.4903G>A (p.Glu1635Lys)

gnomAD frequency: 0.00001  dbSNP: rs200432771

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410023	SCV000489521	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509803	SCV000608213	likely benign	Hereditary cancer-predisposing syndrome	2021-02-17	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769712	SCV000901132	uncertain significance	Breast and/or ovarian cancer	2021-09-23	criteria provided, single submitter	clinical testing
Invitae	RCV001071216	SCV001236507	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1635 of the BRCA1 protein (p.Glu1635Lys). This variant is present in population databases (rs200432771, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 21218378). ClinVar contains an entry for this variant (Variation ID: 41829). 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: 30209399). 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.
GeneDx	RCV000034755	SCV002820826	uncertain significance	not provided	2022-07-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: variant classified as functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with ovarian cancer (Carney et al., 2010); Also known as 5022G>A; This variant is associated with the following publications: (PMID: 22703879, 30209399, 31131967, 21218378)
Baylor Genetics	RCV000410023	SCV004212695	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-22	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034755	SCV000043154	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Brotman Baty Institute, University of Washington	RCV000410023	SCV001243813	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro