Submissions for variant NM_007294.4(BRCA1):c.3845A>T (p.Glu1282Val)

dbSNP: rs80357217

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083561	SCV000076368	likely benign	Hereditary breast ovarian cancer syndrome	2023-08-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000212177	SCV000210158	uncertain significance	not provided	2021-09-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: restoration of proliferation in BRCA1-deficient mouse embryonic stem cells as well as lack of significant sensitivity to cisplatin exposure (Bouwman 2013); Not observed at significant frequency in large population cohorts (Lek 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. RT-PCR analysis suggests the variant does not disrupt normal splicing (Wai 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3964A>T; This variant is associated with the following publications: (PMID: 16267036, 21523855, 22737296, 15343273, 32123317, 23867111)
Ambry Genetics	RCV000162771	SCV000213248	likely benign	Hereditary cancer-predisposing syndrome	2018-09-24	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000112199	SCV000296462	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000112199	SCV000488120	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-01-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212177	SCV000883468	uncertain significance	not provided	2017-11-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162771	SCV000911508	likely benign	Hereditary cancer-predisposing syndrome	2017-02-07	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000162771	SCV003851246	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
PreventionGenetics, part of Exact Sciences	RCV003415808	SCV004109677	uncertain significance	BRCA1-related condition	2023-06-21	criteria provided, single submitter	clinical testing	The BRCA1 c.3845A>T variant is predicted to result in the amino acid substitution p.Glu1282Val. This variant was listed as uncertain in one study of variant classification (Table 2, Judkins et al. 2005. PubMed ID: 16267036). RT-PCR analysis suggests this variant does not impact mRNA splicing (Table S1, Wai et al. 2020. PubMed ID: 32123317). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41243703-T-A). In ClinVar, this variant is interpreted as likely benign/uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/55027/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112199	SCV000144896	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112199	SCV000189340	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-03-16	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003150940	SCV003839269	uncertain significance	not specified	2022-06-24	no assertion criteria provided	clinical testing	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.3845A>T, in exon 10 that results in an amino acid change, p.Glu1282Val. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0004% (dbSNP rs80357217). The p.Glu1282Val change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu1282Val substitution. Functional studies have indicated that this sequence change does not impact function of the BRCA1 protein (PMID: 23867111, 32123317). Due to insufficient evidences, the clinical significance of the p.Glu1282Val change remains unknown at this time.