ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6938-25_6938-19del (rs762815401)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481901 SCV000569581 likely benign not specified 2017-10-09 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000481901 SCV000695010 benign not specified 2020-02-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6938-25_6938-19delGTAATAT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.6e-05 in 230226 control chromosomes, predominantly at a frequency of 0.00077 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (5.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.6938-25_6938-19delGTAATAT has been reported in the literature as IVS12-25del7 in at-least one individual of Chinese ethnicity reportedly affected with benign breast disease (Suter_2004). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Since its previous evaluation as a likely benign variant at our laboratory, we have observed at-least two co-occurrences with other pathogenic variant(s) (BRCA1 c.1518delG , p.Arg507AspfsX25 and BRCA1 c.2800C>T, p.Gln934X) that could explain the phenotype in affected individuals, providing additional supporting evidence for a benign role.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 likely benign. Based on the evidence outlined above, the variant was re-classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000481901 SCV001157075 likely benign not specified 2019-04-16 criteria provided, single submitter clinical testing

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