Submissions for variant NM_000251.3(MSH2):c.698C>G (p.Ser233Cys)

dbSNP: rs587781724

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129911	SCV000184729	likely benign	Hereditary cancer-predisposing syndrome	2022-08-08	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.
Invitae	RCV000465942	SCV000548174	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001551502	SCV001772024	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with cancer (Li et al., 2019); Published functional studies suggest no damaging 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: 18822302, 21120944, 31391288, 33357406)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001551502	SCV002046968	uncertain significance	not provided	2021-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001551502	SCV002506212	uncertain significance	not provided	2022-01-21	criteria provided, single submitter	clinical testing	The MSH2 c.698C>G; p.Ser233Cys variant (rs587781724) is reported in one individual affected with cancer with uncertain significance (Li 2020). This variant is also reported in ClinVar (Variation ID: 141406) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 233 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.562). Due to limited information, the clinical significance of the p.Ser233Cys is uncertain at this time. References Li S et al. Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. J Med Genet. 2020 Jan;57(1):62-69. PMID: 31391288.
Baylor Genetics	RCV003460906	SCV004196294	uncertain significance	Lynch syndrome 1	2023-08-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129911	SCV004356617	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 233 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). This variant has been reported in an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 1/251340 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.
All of Us Research Program, National Institutes of Health	RCV003997535	SCV004830961	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 233 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). This variant has been reported in an individual affected with an unspecified cancer (PMID: 31391288). This variant has been identified in 1/251340 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.