ClinVar Miner

Submissions for variant NM_005431.2(XRCC2):c.596T>C (p.Met199Thr) (rs149099078)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767011 SCV000211843 uncertain significance not provided 2016-09-02 criteria provided, single submitter clinical testing This variant is denoted XRCC2 c.596T>C at the cDNA level, p.Met199Thr (M199T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. XRCC2 Met199Thr was not observed at a significant allele frequency in the 1000 Genomes Project. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. XRCC2 Met199Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within the ATPase domain (Kim 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether XRCC2 Met199Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000767011 SCV000550363 uncertain significance not provided 2019-04-11 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 199 of the XRCC2 protein (p.Met199Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs149099078, ExAC 0.09%). This variant has not been reported in the literature in individuals with XRCC2-related disease. ClinVar contains an entry for this variant (Variation ID: 182996). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance 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.
Fulgent Genetics,Fulgent Genetics RCV000765951 SCV000897372 uncertain significance Fanconi anemia, complementation group U 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV001024734 SCV001186805 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-25 criteria provided, single submitter clinical testing Insufficient evidence

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