Submissions for variant NM_000251.3(MSH2):c.1862G>T (p.Arg621Leu)

gnomAD frequency: 0.00003  dbSNP: rs759263820

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205853	SCV000261128	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 621 of the MSH2 protein (p.Arg621Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with Lynch syndrome (PMID: 21520333, 30702970; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 218040). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000656880	SCV000292624	likely pathogenic	not provided	2021-10-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31391288, 26343386, 30702970, 21120944, 18822302)
Ambry Genetics	RCV000491320	SCV000580563	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-03-14	criteria provided, single submitter	clinical testing	The p.R621L variant (also known as c.1862G>T), located in coding exon 12 of the MSH2 gene, results from a G to T substitution at nucleotide position 1862. The arginine at codon 621 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in individuals whose family history met Amsterdam I/II criteria for Lynch syndrome and/or tumors showed loss of MSH2 and/or MSH6 protein expression on immunohistochemistry (IHC) as well as high microsatellite instability (MSI-H) (Ambry internal data; Fokkema IF et al. Hum. Mutat. 2011 May;32:557-63). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491320	SCV000690024	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 621 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome or Lynch syndrome-associated disease (PMID: 21520333, 30702970; ClinVar SCV000261128.8, SCV000580563.6). Tumor samples from at least two of these individuals demonstrated a loss of MSH2 and MSH6 expression. This variant has also been reported in two individuals with unspecified cancer (PMID: 31391288). This variant has been identified in 1/31364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.1861C>G (p.Arg621Gly) and c.1862G>C (p.Arg621Pro), are considered to be disease-causing (ClinVar variation ID: 408524, 483736), suggesting this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226247	SCV000917704	likely pathogenic	Hereditary nonpolyposis colon cancer	2023-03-17	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1862G>T (p.Arg621Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes. c.1862G>T has been reported in the literature in several individuals affected with Lynch Syndrome and Lynch syndrome-associated cancers (e.g., Salvador_2019, Li_2020, Fokkema_2011). These data indicate that the variant is likely to be associated with disease. At least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH6 c.3699_3702delAGAA, p.Lys1233fsX6; internal testing). At least one publication reports experimental evidence evaluating an impact on mismatch repair (MMR) function, suggesting the variant may have a deleterious effect (e.g., Jia_2021). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as pathogenic (n = 1)/likely pathogenic (n = 3). Based on the emerging consensus evidence outlined above, the variant was re-classified as likely pathogenic.
Baylor Genetics	RCV003462356	SCV004196865	likely pathogenic	Lynch syndrome 1	2023-03-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000201977	SCV000257155	uncertain significance	not specified		no assertion criteria provided	research