Submissions for variant NM_000535.7(PMS2):c.1864A>G (p.Met622Val)

gnomAD frequency: 0.00035  dbSNP: rs370853512

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080254	SCV000261560	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000221658	SCV000273417	likely benign	Hereditary cancer-predisposing syndrome	2017-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000588546	SCV000566510	uncertain significance	not provided	2020-03-24	criteria provided, single submitter	clinical testing	While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors support a deleterious effect.; Observed in individuals undergoing hereditary cancer panel testing for Lynch syndrome-related cancers and/or polyps (Yurgelun 2015); This variant is associated with the following publications: (PMID: 21356188, 11793469, 25980754, 19526325, 16472587)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588546	SCV000697316	uncertain significance	not provided	2017-03-24	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.1864A>G (p.Met622Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the ExAC database in 46/121374 control chromosomes at a frequency of 0.000379, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), however ExAC does not use technology that is able to differentiate between PMS2 and highly homologous psuedogenes, therefore pseudogene intereference cannot be ruled out. The variant has been reported in affected individuals in the literature, without strong evidence for causality. A functional study suggests the binding of PMS2-M622V to MLH1 was consistently decreased, however quantification was not provided (Plon_2011). The variant was classified by one reputable clinical lab as a VUS, and by another as likely benign. Taken together, until additional functional and clinical data becomes available, this variant is classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000221658	SCV000910813	likely benign	Hereditary cancer-predisposing syndrome	2017-03-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000221658	SCV002530235	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-11	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000221658	SCV002819195	benign	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000588546	SCV004223988	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	BP4