ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1126C>T (p.Pro376Ser) (rs730881911)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160888 SCV000211580 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1126C>T at the cDNA level, p.Pro376Ser (P376S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Pro376Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Pro376Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000217986 SCV000278577 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000217986 SCV000690998 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing
Invitae RCV000694862 SCV000823324 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 376 of the PMS2 protein (p.Pro376Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs730881911, ExAC 0.001%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 182803). 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. 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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