Submissions for variant NM_000251.3(MSH2):c.476G>T (p.Arg159Ile)

gnomAD frequency: 0.00001  dbSNP: rs786202921

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165991	SCV000216749	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-13	criteria provided, single submitter	clinical testing	The p.R159I variant (also known as c.476G>T), located in coding exon 3 of the MSH2 gene, results from a G to T substitution at nucleotide position 476. The arginine at codon 159 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
GeneDx	RCV000478310	SCV000572102	uncertain significance	not provided	2016-10-21	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.476G>T at the cDNA level, p.Arg159Ile (R159I) at the protein level, and results in the change of an Arginine to an Isoleucine (AGA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Arg159Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Arg159Ile occurs at a position that is conserved across species and is located in the connector domain (Lützen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Arg159Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780455	SCV000917717	uncertain significance	not specified	2018-07-31	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.476G>T (p.Arg159Ile) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain 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 121412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.476G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001850329	SCV002151333	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-10-18	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 of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 186400). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with isoleucine at codon 159 of the MSH2 protein (p.Arg159Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine.
All of Us Research Program, National Institutes of Health	RCV003995470	SCV004829704	uncertain significance	Lynch syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with isoleucine at codon 159 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/31398 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.