ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1002T>G (p.His334Gln) (rs544942885)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509997 SCV000608268 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000509997 SCV000683388 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590212 SCV000694489 uncertain significance not provided 2017-03-02 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1002T>G (p.His334Gln) variant causes a missense change involving a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/120286 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). One clinical diagnostic laboratory and one reputable database 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. 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 RCV000463547 SCV000549602 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 334 of the BRCA2 protein (p.His334Gln). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs544942885, ExAC 0.006%). This variant has not been reported in the literature in individuals with BRCA2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000239056 SCV000296501 uncertain significance Breast-ovarian cancer, familial 2 2016-05-26 criteria provided, single submitter clinical testing

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