ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8007A>G (p.Arg2669=) (rs143999963)

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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 RCV000565818 SCV000665951 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Color RCV000565818 SCV000903268 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Counsyl RCV000662966 SCV000785944 uncertain significance Breast-ovarian cancer, familial 2 2018-01-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000231287 SCV000494390 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-04-04 criteria provided, single submitter clinical testing Variant Summary: c.8007A>G is a synonymous mutation that occurrs at a non-conserved position. MutationTaster predicts the variant to be disease causing; 3/5 Alamut algorithms predict a gain of a splice donor site, however, no functional studies have been carried out to support these predictions. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0008% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). One reputable clinical lab has classified the variant as a VUS. Taken together, the variant was classified as a VUS - possibly benign until additional information becomes available.
Integrated Genetics/Laboratory Corporation of America RCV000590364 SCV000695119 uncertain significance not provided 2016-04-04 criteria provided, single submitter clinical testing Variant Summary: c.8007A>G is a synonymous mutation that occurrs at a non-conserved position. MutationTaster predicts the variant to be disease causing; 3/5 Alamut algorithms predict a gain of a splice donor site, however, no functional studies have been carried out to support these predictions. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0008% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). One reputable clinical lab has classified the variant as a VUS. Taken together, the variant was classified as a VUS-possibly benign until additional information becomes available.
Invitae RCV000231287 SCV000283329 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change affects codon 2669 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 (rs143999963, ExAC 0.002%). This variant has been reported in an individual referred for BRCA1 and BRCA2 testing (PMID: 25556971). ClinVar contains an entry for this variant (Variation ID: 188439). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing. In an experimental study, this variant lead to a partial splicing defect where exon 18 was skipped in ~15% of the transcripts (PMID: 28339459). The clinical significance of this result is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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