ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.807A>G (p.Thr269=) (rs142072914)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164151 SCV000214767 likely benign Hereditary cancer-predisposing syndrome 2014-03-17 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000495590 SCV000579015 likely benign Breast-ovarian cancer, familial 2 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
GeneDx RCV000600725 SCV000719675 likely benign not specified 2017-05-19 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.
Integrated Genetics/Laboratory Corporation of America RCV000600725 SCV000916901 uncertain significance not specified 2018-06-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.807A>G results in a synonymous change. Several computational tools predict an impact on normal splicing: Two predict the variant creates a 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.2e-06 in 240508 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.807A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x) and uncertain significance (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000528059 SCV000635634 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-07 criteria provided, single submitter clinical testing This sequence change affects codon 269 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. This variant is present in population databases (rs142072914, ExAC 0.006%) but has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 184826). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare silent change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759669 SCV000889151 likely benign not provided 2017-10-18 criteria provided, single submitter clinical testing

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