Submissions for variant NM_000251.3(MSH2):c.2178G>C (p.Met726Ile)

gnomAD frequency: 0.00002  dbSNP: rs587782396

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131413	SCV000186390	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The p.M726I variant (also known as c.2178G>C), located in coding exon 13 of the MSH2 gene, results from a G to C substitution at nucleotide position 2178. The methionine at codon 726 is replaced by isoleucine, an amino acid with highly similar properties. In a Russian study, this alteration was detected in 2/711 hereditary breast cancer patients and 0/492 healthy controls (Nikitin AG et al. Front Oncol, 2020 May;10:666). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This alteration was seen in 0/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). 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 alteration remains unclear.
Invitae	RCV000524379	SCV000284140	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131413	SCV000537582	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 726 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 been reported in individuals affected with breast cancer (PMID: 32547938). This variant has been identified in 6/251480 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.
GeneDx	RCV000767207	SCV000565200	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer or melanoma (Yehia et al., 2018; Nikitin et al., 2020); This variant is associated with the following publications: (PMID: 29684080, 32547938)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486473	SCV000601459	uncertain significance	not specified	2017-06-08	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000767207	SCV002009333	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000767207	SCV002063857	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000486473	SCV002066661	uncertain significance	not specified	2020-11-03	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2178G>C, in exon 13 that results in an amino acid change, p.Met726Ile. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders and has been described in the gnomAD database with a frequency of 0.005% in the European sub-population (dbSNP rs587782396). The p.Met726Ile change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Met726Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Met726Ile change remains unknown at this time.
Baylor Genetics	RCV003467174	SCV004193913	uncertain significance	Lynch syndrome 1	2023-10-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532570	SCV004719633	uncertain significance	MSH2-related disorder	2024-02-08	criteria provided, single submitter	clinical testing	The MSH2 c.2178G>C variant is predicted to result in the amino acid substitution p.Met726Ile. This variant has been reported in several individuals with breast cancer (Table S2, Nikitin et al. 2020. PubMed ID: 32547938; Table S2, Krivokuca et al. 2021. PubMed ID: 34284872; Table S6, Akcay et al. 2020. PubMed ID: 32658311). This variant is reported in 0.0053% of alleles in individuals of European (non-Finnish) descent in gnomAD and it has been classified as uncertain and likely benign by other institutions in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/142341/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003998103	SCV004825725	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 726 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). 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 individuals affected with breast cancer (PMID: 32547938). This variant has been identified in 6/251480 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000227062	SCV000592541	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Met726Ile variant was not identified in our literature search, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, GeneInsight COGR, BIC or UMD. It was identified in Clinvitae (uncertain significance), and ClinVar database (1X classified as a variant of uncertain significance by Ambry Genetics). The p.Met726 residue is conserved in mammals and other organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein, but this information is not very predictive of pathogenicity. 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 unknown significance.