Submissions for variant NM_000251.3(MSH2):c.2110A>G (p.Ile704Val)

gnomAD frequency: 0.00001  dbSNP: rs730881764

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590168	SCV000211197	uncertain significance	not provided	2023-08-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18822302, 21120944)
Ambry Genetics	RCV000160601	SCV000217346	likely benign	Hereditary cancer-predisposing syndrome	2021-12-16	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590168	SCV000696235	uncertain significance	not provided	2016-02-08	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a conserved nucleotide and results in a replacement of an Isoleucine (I) with a Valine (V). Both residues are medium size and hydrophobic, therefore this Isoleucine to a Valine substitution likely does not alter the physico-chemical properties of the protein. 4/5 in silico tools predict the variant to be neutral. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0016% which does not exceed the maximal expected allele frequency of a disease causing MSH2 allele (0.057%). To our knowledge, the variant has not been reported in affected patients and in vitro/vivo studies to assess the functional impact of the variant were not published either. Clinical diagnostic laboratories classify variant as Uncertain via ClinVar (without evidence t =o independently evaluate). Due to the lack of clinical and functional data, the variant was classified as a variant of uncertain significance until more information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000160601	SCV000908326	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 704 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant behaved as neutral in a 6-thioguanine resistance based mismatch repair assay (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 2/251478 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.
Invitae	RCV000796598	SCV000936118	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-03	criteria provided, single submitter	clinical testing
Mendelics	RCV002247555	SCV002518264	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998477	SCV004827818	uncertain significance	Lynch syndrome	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 704 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant behaved as neutral in a 6-thioguanine resistance based mismatch repair assay (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 2/251478 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.