Submissions for variant NM_000251.3(MSH2):c.581T>C (p.Ile194Thr)

gnomAD frequency: 0.00002  dbSNP: rs730881778

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212589	SCV000211239	uncertain significance	not provided	2014-10-09	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.581T>C at the cDNA level, p.Ile194Thr (I194T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). In a yeast based functional assay, MSH2 Ile194Thr was not shown to cause any mismatch repair defects (Martinez 2010). MSH2 Ile194Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ile194Thr occurs at a position that is well conserved across species and is located in the connector domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Ile194Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000160638	SCV000216832	likely benign	Hereditary cancer-predisposing syndrome	2022-12-30	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	RCV000556928	SCV000625439	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160638	SCV000903531	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 194 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), and retained wild type MSH2 mismatch repair activity in yeast (PMID: 20176959). This variant has been reported in an individual affected with hereditary breast or ovarian cancer (PMID: 30262796). This variant has not been identified 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	RCV001356798	SCV004828466	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 194 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), and retained wild type MSH2 mismatch repair activity in yeast (PMID: 20176959). This variant has been reported in an individual affected with hereditary breast or ovarian cancer (PMID: 30262796). This variant has not been identified 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356798	SCV001552063	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Ile194Thr variant was identified in the literature in functional analysis of human mismatch repair gene mutations using S. cerevisiae-based assay and had no significant difference between mutation and wild-type rates (Martinez 2010). The variant was also identified in dbSNP (ID: rs730881778) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, GeneDx and Ambry Genetics). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 1 of 246194 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111648 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ile194 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212589	SCV001978527	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212589	SCV001979504	uncertain significance	not provided		no assertion criteria provided	clinical testing