ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8737G>C (p.Asp2913His) (rs144322424)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216210 SCV000275482 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000586685 SCV000695177 uncertain significance not provided 2017-02-14 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8737G>C (p.Asp2913His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/119098 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Reportedly, this variant co-occurred with truly deleterious mutation in the BRCA1 gene, suggesting a non-disease causing nature of this variant, however more definitive data are needed to classify this variant with confidence. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000527864 SCV000635684 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 2913 of the BRCA2 protein (p.Asp2913His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs144322424, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 231585). Experimental studies have shown that this missense change does not have a significant effect on the homology directed repair activity of BRCA2 (PMID: 29884841). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586685 SCV000889164 uncertain significance not provided 2017-09-12 criteria provided, single submitter clinical testing

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