Submissions for variant NM_000535.7(PMS2):c.502G>A (p.Val168Met) (rs762645507)

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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	RCV000165453	SCV000216183	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-20	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence
GeneDx	RCV000481889	SCV000569478	uncertain significance	not provided	2018-05-29	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.502G>A at the cDNA level, p.Val168Met (V168M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Val168Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Val168Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color	RCV000165453	SCV000686213	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-09	criteria provided, single submitter	clinical testing
Invitae	RCV000822639	SCV000963449	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine with methionine at codon 168 of the PMS2 protein (p.Val168Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs762645507, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185940). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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