Submissions for variant NM_000251.3(MSH2):c.759G>A (p.Met253Ile)

gnomAD frequency: 0.00001  dbSNP: rs1060502021

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467943	SCV000548266	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 253 of the MSH2 protein (p.Met253Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408527). 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 not expected to disrupt MSH2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV000568397	SCV000662257	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	The p.M253I variant (also known as c.759G>A), located in coding exon 4 of the MSH2 gene, results from a G to A substitution at nucleotide position 759. The methionine at codon 253 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and isoleucine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000568397	SCV000904248	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 253 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). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant was reported in 1/60466 cases and 0/53461 unaffected controls (PMID: 33471991). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001171949	SCV001469555	uncertain significance	not provided	2019-09-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568397	SCV002526741	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
GeneDx	RCV001171949	SCV003921570	uncertain significance	not provided	2023-05-01	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; Observed in an individual with breast cancer (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 28481359, 18822302, 21120944, 33471991)
Myriad Genetics, Inc.	RCV003335335	SCV004043200	likely benign	Lynch syndrome 1	2023-09-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
All of Us Research Program, National Institutes of Health	RCV004000790	SCV004829093	uncertain significance	Lynch syndrome	2023-07-22	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 253 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). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant was reported in 1/60466 cases and 0/53461 unaffected controls (PMID: 33471991). 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.