Submissions for variant NM_000535.7(PMS2):c.1883G>A (p.Arg628Gln) (rs587780044)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115667	SCV000149576	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1883G>A at the cDNA level, p.Arg628Gln (R628Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located in the MLH1 interaction domain and the nuclear localization sequence (Kondo 2001, Leong 2009). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether PMS2 Arg628Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000214212	SCV000274494	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence;In silico models in agreement (benign);Structural Evidence
Invitae	RCV000559426	SCV000625563	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2019-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 628 of the PMS2 protein (p.Arg628Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587780044, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127767). 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 glutamine amino acid residue is 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 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.
Color	RCV000214212	SCV000911523	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-26	criteria provided, single submitter	clinical testing

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