Submissions for variant NM_000251.3(MSH2):c.641G>T (p.Arg214Ile)

gnomAD frequency: 0.00001  dbSNP: rs763298811

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204214	SCV000261075	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-06	criteria provided, single submitter	clinical testing	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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 220492). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is present in population databases (rs763298811, gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 214 of the MSH2 protein (p.Arg214Ile).
Ambry Genetics	RCV000565649	SCV000662308	likely benign	Hereditary cancer-predisposing syndrome	2021-12-21	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.
Color Diagnostics, LLC DBA Color Health	RCV000565649	SCV000911921	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with isoleucine at codon 214 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 does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/245190 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001556775	SCV001778413	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: restored mismatch repair (MMR) function in a MSH2 knockout cell line (Jia et al., 2020); This variant is associated with the following publications: (PMID: 25822088, 31857677, 18822302, 21120944, 33357406)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315421	SCV004015215	uncertain significance	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with isoleucine at codon 214 of the MSH2 protein (p.Arg214Ile). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant is present in population databases (rs763298811, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 220492) with 4 submissions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001556775	SCV004221010	uncertain significance	not provided	2023-03-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000066 (1/152204 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in tumors of individuals affected with uterine endometrioid carcinoma (PMID: 31857677 (2020)) and desmoplastic infantile ganglioglioma (PMID: 35370679 (2022)). A functional study showed that the variant has neutral effects on DNA mismatch repair function in vivo using a 6-thioguanine sensitivity assay (PMID: 33357406 (2021)). However, analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997641	SCV004830872	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with isoleucine at codon 214 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 does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/245190 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.