ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5498A>G (p.Asn1833Ser) (rs587782601)

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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 RCV000131959 SCV000187016 likely benign Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign)
Color RCV000131959 SCV000906108 likely benign Hereditary cancer-predisposing syndrome 2018-07-11 criteria provided, single submitter clinical testing
GeneDx RCV000432115 SCV000517306 likely benign not specified 2017-04-11 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 RCV000432115 SCV000919028 uncertain significance not specified 2018-11-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5498A>G (p.Asn1833Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 276472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5498A>G, has been reported in the literature in one family affected with Hereditary Breast and Ovarian Cancer (Zuntini_2018). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.4327C>T, p.Arg1443X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign x2, VUS x2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000206165 SCV000261215 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1833 of the BRCA2 protein (p.Asn1833Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs587782601, ExAC 0.02%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142634). 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 RCV000432115 SCV000600644 uncertain significance not specified 2016-09-26 criteria provided, single submitter clinical testing

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