Submissions for variant NM_000059.4(BRCA2):c.7805+13A>G

gnomAD frequency: 0.00019  dbSNP: rs149769332

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160247	SCV000210662	benign	not specified	2014-08-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000199590	SCV000254213	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579869	SCV000683908	likely benign	Hereditary cancer-predisposing syndrome	2016-06-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160247	SCV000695103	benign	not specified	2021-07-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7805+13A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic intronic alternate 3' acceptor site. However, these predictions have not been corraborated by published functional studies, which have demonstrated no impact on normal splicing and have categorized this variant as a class 1 (benign) variant (example, Montalban_2019). The variant allele was found at a frequency of 4e-05 in 251174 control chromosomes, predominantly at a frequency of 0.00037 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7805+13A>G has been reported in the literature as a VUS in individuals from families affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple co-occurrences with other pathogenic variant(s) have been reported in the UMD database, literature and observed at our laboratory (UMD database and Montalban_2019-BRCA1 c.3748G>T, p.Glu1250X; our laboratory-BRCA1 c.4986+6T>C), providing supporting evidence for a benign role. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=1)/likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign.
Counsyl	RCV000662386	SCV000784790	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000662386	SCV001139193	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000199590	SCV002025830	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353613	SCV000592142	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.7805+13A>G variant was not identified in the literature, but was identified in dbSNP (ID: rs149769332), and in the UMD (4X as an unclassified variant). The variant was identified by the Exome Variant Server project in 1 of 4406 African American alleles (frequency: 0.0002) and in the 1000 Genomes Project in 1 allele (frequency 0.0005), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The c.7805+13A>G variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	RCV000199590	SCV000916368	benign	Hereditary breast ovarian cancer syndrome	2019-03-01	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001706065	SCV001905852	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001706065	SCV001957460	likely benign	not provided		no assertion criteria provided	clinical testing