Submissions for variant NM_000179.3(MSH6):c.38A>C (p.Lys13Thr)

dbSNP: rs41294988

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160705	SCV000211335	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate intermediate MMR activity as compared to wild-type (Drost et al., 2020); This variant is associated with the following publications: (PMID: 19389263, 23621914, 21153778, 26333163, Yambert2022[article], 18033691, 31965077)
Invitae	RCV000627725	SCV000551144	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 13 of the MSH6 protein (p.Lys13Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 36596). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH6 function (PMID: 31965077). 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.
Ambry Genetics	RCV000569787	SCV000662392	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-18	criteria provided, single submitter	clinical testing	The p.K13T variant (also known as c.38A>C), located in coding exon 1 of the MSH6 gene, results from an A to C substitution at nucleotide position 38. The lysine at codon 13 is replaced by threonine, an amino acid with similar properties. This alteration was identified in one of 932 colorectal cancer patients diagnosed under 55 years of age and was not seen in any of the 1104 control individuals; however, this individual’s tumor showed microsatellite stability and presence of MSH6 staining on immunohistochemistry and was therefore classified as "undefined" (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569787	SCV000685459	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 13 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant retained approximately 50% of wild-type mismatch repair activity (PMID: 31965077). This variant has been reported in an individual with mismatch repair stable colorectal cancer (PMID: 18033691). This variant has not been identified 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	RCV000662751	SCV000785534	uncertain significance	Lynch syndrome 5	2017-09-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818192	SCV002069377	uncertain significance	not specified	2018-08-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662751	SCV004019103	uncertain significance	Lynch syndrome 5	2023-03-30	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.
Baylor Genetics	RCV003466879	SCV004197610	uncertain significance	Endometrial carcinoma	2023-10-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160705	SCV004222019	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with colorectal cancer (PMID: 18033691 (2008)). Published functional studies to determine the effect of this variant on protein function were inconclusive (PMID: 31965077 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000030274	SCV004832277	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 13 of the MSH6 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 an individual affected with colorectal cancer (PMID: 18033691). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030274	SCV000052941	uncertain significance	Lynch syndrome	2015-10-02	no assertion criteria provided	clinical testing