Submissions for variant NM_000251.3(MSH2):c.317G>A (p.Arg106Lys)

gnomAD frequency: 0.00009  dbSNP: rs41295286

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076564	SCV000107594	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
GeneDx	RCV000588805	SCV000149434	likely benign	not provided	2019-11-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22949387, 22290698, 18033691, 16736289)
Ambry Genetics	RCV000115525	SCV000172850	benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Pathway Genomics	RCV000172812	SCV000223778	benign	Lynch syndrome 1	2014-10-30	criteria provided, single submitter	clinical testing
Invitae	RCV001083191	SCV000284165	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202010	SCV000696260	likely benign	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.317G>A (p.Arg106Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of 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 7.1e-05 in 253718 control chromosomes (gnomAD and publication). This frequency is not higher than estimated for a pathogenic variant in MSH2 causing Lynch Syndrome (7.1e-05 vs 0.00057), allowing no conclusion about variant significance. c.317G>A has been reported in a proband from LS family with lack of co-segregation of this variant with disease. This patient also carried a pathogenic variant in MLH1, which could explain the patients phenotype (Spaepen_2006). The variant of interest has also been reported in a case-control study with comparable allele frequency detected in the control and case cohorts (Barnetson_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18033691, 16736289, 22290698, 22949387, 31569399). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172812	SCV000744265	benign	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115525	SCV000910795	benign	Hereditary cancer-predisposing syndrome	2016-10-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588805	SCV001134360	likely benign	not provided	2021-03-11	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202010	SCV002552191	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149753	SCV003837613	likely benign	Breast and/or ovarian cancer	2022-09-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202010	SCV000257184	uncertain significance	not specified		no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000202010	SCV001799568	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000588805	SCV001925834	likely benign	not provided		no assertion criteria provided	clinical testing