Submissions for variant NM_000179.3(MSH6):c.998C>T (p.Thr333Ile)

gnomAD frequency: 0.00001  dbSNP: rs587781983

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130382	SCV000185238	likely benign	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000212639	SCV000211344	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with Lynch syndrome who also harbored a pathogenic MLH1 variant and in an individual with pancreatic cancer (Simbolo et al., 2015; Paduano et al., 2022); This variant is associated with the following publications: (PMID: 28717660, 18523027, 27311873, 31422574, 35886069, 26300997)
Invitae	RCV000475028	SCV000551279	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 333 of the MSH6 protein (p.Thr333Ile). This variant is present in population databases (rs587781983, gnomAD 0.007%). This missense change has been observed in individual(s) with Lynch syndrome, however, in that individual a pathogenic allele was also identified in the MLH1 gene, which suggests that this c.998C>T variant was not the primary cause of disease (PMID: 26300997). ClinVar contains an entry for this variant (Variation ID: 141751). 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 MSH6 protein function with a negative predictive value of 95%. 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.
Mendelics	RCV000708861	SCV000837875	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212639	SCV000889514	uncertain significance	not provided	2023-03-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000032 (1/31406 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with Lynch syndrome who also carried a pathogenic variant in the MLH1 gene, suggesting the MSH6 c.998C>T (p.Thr333Ile) variant may not the primary cause of disease. In addition, this variant has been observed in an individual with pancreatic cancer (PMID: 35886069 (2022)), and in several breast cancer cases and a control individual in a large-scale breast cancer association study (see LOVD (http://databases.lovd.nl/shared/genes/MSH6) and PMID: 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000130382	SCV000902968	benign	Hereditary cancer-predisposing syndrome	2015-09-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000986711	SCV001135799	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000986711	SCV002526081	uncertain significance	Lynch syndrome 5	2022-05-24	criteria provided, single submitter	clinical testing	The MSH6 c.998C>T (p.Thr333Ile) missense change has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). In silico tools are inconclusive about the effect of this variant on protein function, and to our knowledge functional assays have not been performed. This variant has been reported in an individual with Lynch syndrome who harbored a pathogenic variant in MLH1 (BP5; PMID: 26300997). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP5.
Sema4, Sema4	RCV000130382	SCV002536378	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-20	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000986711	SCV003807532	uncertain significance	Lynch syndrome 5	2023-01-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated, BP4 supporting
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130382	SCV004014898	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460924	SCV004195578	uncertain significance	Endometrial carcinoma	2023-08-18	criteria provided, single submitter	clinical testing