ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6841+3A>T (rs81002825)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485747 SCV000571895 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6841+3A>T or IVS11+3A>T and consists of an A>T nucleotide substitution at the +3 position of intron 11 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7069+3A>T. Multiple in silico models predict this variant to damage the nearby natural donor site and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 c.6841+3A>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is not conserved across species. Based on currently available information, it is unclear whether BRCA2 c.6841+3A>T is pathogenic or benign. We consider it to be a variant of uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113657 SCV000146950 uncertain significance Breast-ovarian cancer, familial 2 2001-02-16 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000515769 SCV000611871 likely benign Breast cancer, susceptibility to 2017-03-07 no assertion criteria provided research The BRCA2 variant designated as NM_000059.3:c.6841+3A>T is classified as likely benign. The likelihood ratio from cosegregation analysis of one family was 2.6, which is considered weak evidence supporting pathogenicity (Thompson et al, 2003, PMID:12900794). However, splice analysis of this variant indicates that exon 11 skipping occurs in less than 5% of RNA transcripts. Although the results of cosegregation and splice analysis are not concordant, the splice analysis provides strong evidence that the variant has no effect on cancer risk. Overall, the combined results are consistent with a classification of likely benign. This variant is not predicted to alter BRCA2 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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