Submissions for variant NM_000179.3(MSH6):c.3605T>C (p.Met1202Thr)

gnomAD frequency: 0.00001  dbSNP: rs587779273

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129370	SCV000184134	likely benign	Hereditary cancer-predisposing syndrome	2018-06-26	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.
GeneDx	RCV000212685	SCV000211323	uncertain significance	not provided	2021-01-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26333163, 22290698, 21520333, 23443670)
Invitae	RCV000524181	SCV000261076	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129370	SCV000690379	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1202 of the MSH6 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. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/31382 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.
Counsyl	RCV000662842	SCV000785702	uncertain significance	Lynch syndrome 5	2017-11-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764434	SCV000895491	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662842	SCV004019059	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987347	SCV004804325	uncertain significance	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3605T>C (p.Met1202Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251442 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3605T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; five submitters classified the variant as uncertain significance, while two classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997094	SCV004835104	uncertain significance	Lynch syndrome	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1202 of the MSH6 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. This variant has been reported in individuals affected with suspected Lynch syndrome (Insight-database.org). This variant has been identified in 1/31382 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.