Submissions for variant NM_000251.3(MSH2):c.1254A>G (p.Ile418Met)

gnomAD frequency: 0.00001  dbSNP: rs751431238

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200127	SCV000254379	benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564423	SCV000662299	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	The p.I418M variant (also known as c.1254A>G), located in coding exon 7 of the MSH2 gene, results from an A to G substitution at nucleotide position 1254. The isoleucine at codon 418 is replaced by methionine, an amino acid with highly similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also identified in multiple individuals diagnosed with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; Nassar A et al. Genes (Basel), 2022 Dec;14:). This amino acid position is not well conserved in available 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	RCV000564423	SCV000689966	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 418 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with early-onset ovarian and colorectal cancers (PMID: 30238922, 34761457). This variant has been identified in 2/251294 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.
Fulgent Genetics, Fulgent Genetics	RCV000765666	SCV000897008	uncertain significance	Lynch syndrome 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001589078	SCV001824988	likely benign	not provided	2021-03-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with endometrial cancer (Ozdemir 2019); This variant is associated with the following publications: (PMID: 30238922)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155118	SCV003844385	uncertain significance	not specified	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1254A>G (p.Ile418Met) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251294 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1254A>G has been reported in the literature in individuals affected with various types of cancer, without strong evidence for causality (Ozdemir_2019, Li_2020, Sandoval_2021, Mikaeel_2022). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV003316110	SCV004018692	likely benign	Lynch syndrome 1	2023-06-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004528987	SCV004106394	uncertain significance	MSH2-related disorder	2023-04-04	criteria provided, single submitter	clinical testing	The MSH2 c.1254A>G variant is predicted to result in the amino acid substitution p.Ile418Met. This variant has been reported in individuals with Lynch syndrome cancers and individuals with breast cancer (Table 2, Özdemir et al 2019. PubMed ID: 30238922; Table S5, Li et al. 2020. PubMed ID: 31391288; Table S4, Sandoval et al. 2021. PubMed ID: 33606809; Table S4, PubMed ID: 34761457). This variant is reported in 2 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/2-47657058-A-G). It has conflicting interpretations of benign, likely benign, and uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/216341/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003316110	SCV004194554	uncertain significance	Lynch syndrome 1	2023-06-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997012	SCV004832701	uncertain significance	Lynch syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 418 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual with an unspecified cancer and microsatellite instability (PMID: 31391288) and an individual affected with endometrial cancer (PMID: 30238922). This variant has been identified in 2/251294 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.