ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.949A>G (p.Met317Val) (rs587782502)

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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 RCV000131642 SCV000186668 likely benign Hereditary cancer-predisposing syndrome 2017-10-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene,In silico models in agreement (benign)
Color RCV000131642 SCV000910940 likely benign Hereditary cancer-predisposing syndrome 2016-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000485286 SCV000565990 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing This variant is denoted NBN c.949A>G at the cDNA level, p.Met317Val (M317V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant was observed in at least one individual with ovarian cancer (Ramus 2015). NBN Met317Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). NBN Met317Val is located within the BRCT2 domain (Damiola 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether NBN Met317Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000477065 SCV000553110 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 317 of the NBN protein (p.Met317Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs587782502, ExAC 0.001%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 142497). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional 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.

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