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

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115667	SCV000149576	uncertain significance	not provided	2020-02-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 25224212, 29596542)
Ambry Genetics	RCV000214212	SCV000274494	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Insufficient or conflicting evidence;Structural Evidence
Invitae	RCV000559426	SCV000625563	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-08-27	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 Health, Inc	RCV000214212	SCV000911523	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420821	SCV001623201	uncertain significance	not specified	2021-04-26	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1883G>A (p.Arg628Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251428 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1883G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.