Submissions for variant NM_000179.3(MSH6):c.2992T>A (p.Ser998Thr)

gnomAD frequency: 0.00001  dbSNP: rs730881800

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160685	SCV000211306	uncertain significance	not provided	2021-01-14	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 has a deleterious effect on protein structure/function; Observed in an individual with a personal history of colorectal cancer in published literature (Limburg 2011); This variant is associated with the following publications: (PMID: 30798936, 21056691, 23621914)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168112	SCV000218768	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 998 of the MSH6 protein (p.Ser998Thr). This variant is present in population databases (rs730881800, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 21056691). ClinVar contains an entry for this variant (Variation ID: 182639). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (PMID: 23621914). 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.
Color Diagnostics, LLC DBA Color Health	RCV000579908	SCV000685345	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000662434	SCV000784890	uncertain significance	Lynch syndrome 5	2017-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579908	SCV001178986	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The p.S998T variant (also known as c.2992T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 2992. The serine at codon 998 is replaced by threonine, an amino acid with similar properties. This variant was observed in a female patient diagnosed with rectal cancer at age 45 (Limburg PJ et al, 2011 Jun;9:497-502). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000160685	SCV002010100	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662434	SCV004018962	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.
All of Us Research Program, National Institutes of Health	RCV003998498	SCV004834411	uncertain significance	Lynch syndrome	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 998 of the MSH6 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 an individual affected with early-onset colorectal cancer, however, they did not meet Amsterdam criteria and their tumor showed normal expression of MLH1, MSH2, and MSH6 via immunohistochemistry analysis (PMID: 21056691). This variant has been identified in 3/237444 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.