Submissions for variant NM_000059.4(BRCA2):c.7436-4A>G

gnomAD frequency: 0.00001  dbSNP: rs81002904

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084165	SCV000073228	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001353462	SCV000210421	likely benign	not provided	2021-05-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31191615, 31143303)
Ambry Genetics	RCV000164776	SCV000215452	benign	Hereditary cancer-predisposing syndrome	2015-04-30	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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	RCV000768634	SCV000219393	uncertain significance	Breast and/or ovarian cancer	2017-07-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001353462	SCV000600750	likely benign	not provided	2022-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168599	SCV000695067	likely benign	not specified	2024-04-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7436-4A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. In addition, at least two publications reported experimental evidence demonstrating that the variant does not impact normal splicing, in either patient derived mRNA (Wangensteen_2019) or in a minigene assay (Fraile-Bethencourt_2019). The variant allele was found at a frequency of 1.6e-05 in 251022 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7436-4A>G has been reported in the literature in at least one individual screened for Hereditary Breast and Ovarian Cancer (Wangensteen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31191615, 31143303). ClinVar contains an entry for this variant (Variation ID: 38097). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000164776	SCV000910822	likely benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001353462	SCV002048424	likely benign	not provided	2020-10-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164776	SCV002531857	likely benign	Hereditary cancer-predisposing syndrome	2020-12-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168599	SCV002551502	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803065	SCV004834180	likely benign	BRCA2-related cancer predisposition	2024-07-29	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031679	SCV000054286	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031679	SCV000147086	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353462	SCV000592110	uncertain significance	not provided		no assertion criteria provided	clinical testing	The c.7436-4A>G variant has not been previously identified in the literature but has been identified in one individual with breast cancer in our laboratory. This individual met the ministry of health of ontario categories 7 (two cases of breast cancer, both <50 years, in first or second-degree relatives) and 10 (three or more cases of breast or ovarian cancer at any age). This variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Computational or in-silico analyses do not demonstrate altered splicing in 4 of the splice prediction programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE, HumanSpliceFinder), increasing the possibility that this may be a benign variant. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. Therefore this variant is a variant of unknown significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001084165	SCV002050303	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532456	SCV004721782	likely benign	BRCA2-related disorder	2020-09-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).