ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7805+13A>G (rs149769332)

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Total submissions: 10
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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 and ovarian cancer syndrome 2020-11-23 criteria provided, single submitter clinical testing
Color Health, Inc 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 2 2017-01-18 criteria provided, single submitter clinical testing
Mendelics RCV000662386 SCV001139193 likely benign Breast-ovarian cancer, familial 2 2019-05-28 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 and 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
Human Genetics - Radboudumc,Radboudumc RCV001706065 SCV001957460 likely benign not provided no assertion criteria provided clinical testing

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