Submissions for variant NM_000251.3(MSH2):c.1379T>C (p.Met460Thr)

gnomAD frequency: 0.00001  dbSNP: rs1553361303

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567509	SCV000673868	likely benign	Hereditary cancer-predisposing syndrome	2022-12-22	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.
Color Diagnostics, LLC DBA Color Health	RCV000567509	SCV000689981	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-06	criteria provided, single submitter	clinical testing
Invitae	RCV000685208	SCV000812681	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 460 of the MSH2 protein (p.Met460Thr). 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: 485825). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759100	SCV000888205	uncertain significance	not provided	2018-02-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000567509	SCV002528839	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
Baylor Genetics	RCV003459384	SCV004194545	uncertain significance	Lynch syndrome 1	2023-06-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001116	SCV004833219	uncertain significance	Lynch syndrome	2023-06-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000759100	SCV001550322	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Met394Thr variant was not identified in the literature nor was it identified in dbSNP, Cosmic or the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified in ClinVar (classified as a VUS by Ambry Genetics, Color, Invitae and Quest Diagnostics) and LOVD 3.0. The p.Met394 residue is not 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.