Submissions for variant NM_000059.4(BRCA2):c.6841+3A>T

dbSNP: rs81002825

Total submissions: 3

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, susceptibility to, 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.