Submissions for variant NM_000179.3(MSH6):c.383G>T (p.Arg128Leu)

dbSNP: rs63750143

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165162	SCV000215873	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	The p.R128L variant (also known as c.383G>T), located in coding exon 2 of the MSH6 gene, results from a G to T substitution at nucleotide position 383. The arginine at codon 128 is replaced by leucine, an amino acid with dissimilar properties. One group proposed a classification of benign for p.R128L after they identified this alteration in an endometrial cancer patient not satisfying testing criteria for HNPCC/Lynch syndrome and demonstrated no associated impairment in MSH2-interaction or mismatch repair activity in vitro (Kariola R, Br. J. Cancer 2004 Oct; 91(7):1287-92; Hampel H, Cancer Res. 2006 Aug; 66(15):7810-7). Another study using an oligonucleotide-directed mutagenesis screen in mouse embryonic stem cells did not find this alteration to be pathogenic (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). 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.
GeneDx	RCV000485426	SCV000571560	uncertain significance	not provided	2022-07-28	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: does not negatively impact MMR activity, but the N-terminus, where this variant is located, may not be required for in vitro MMR activity and may impact other functions (Kariola et al., 2004; Li et al., 2013); Observed in individuals with Lynch syndrome-related cancers, with at least one tumor showing IHC results and MLH1 promoter hypermethylation suggesting a sporadic cause (Kariola et al., 2004; Hampel et al., 2006; Yurgelun et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21120944, 23621914, 28531214, 9595616, 18484749, 16885385, 15354210, 24145353, 28135145, 31391288, 33471991)
Invitae	RCV000545223	SCV000624931	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 128 of the MSH6 protein (p.Arg128Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with endometrial cancer and colorectal cancer (PMID: 15354210, 28135145). ClinVar contains an entry for this variant (Variation ID: 89473). 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%. Experimental studies have shown that this missense change does not substantially affect MSH6 function (PMID: 15354210). 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.
Fulgent Genetics, Fulgent Genetics	RCV000765680	SCV000897022	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165162	SCV001352506	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 128 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 reported that the variant protein retained MSH2 binding and complementation of DNA mismatch repair (MMR) in a MMR-deficient cell line (PMID: 15354210). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 15354210, 28135145; ClinVar SCV000503524.1), and in an individual with unspecified cancer (PMID: 31391288). In an individual affected with endometrial cancer, a sample showed MLH1 promoter methylation and the absence of MLH1 and presence of MSH6 by immunohistochemistry, which indicates that the disease phenotype may be due to the MLH1 epigenetic change (PMID: 15354210). 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.
Sema4, Sema4	RCV000165162	SCV002528078	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-13	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265595	SCV002547884	uncertain significance	not specified	2022-05-05	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.383G>T (p.Arg128Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.383G>T has been reported in the literature in individuals affected with Lynch Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kariola_2004). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000074941	SCV004826688	uncertain significance	Lynch syndrome	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 128 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study reported that the variant protein retained MSH2 binding and complementation of DNA mismatch repair (MMR) in a MMR-deficient cell line (PMID: 15354210). This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 28135145, 15354210 and ClinVar RCV000074941.3). In one case, the endometrial cancer sample showed MLH1 promoter methylation and the absence of MLH1 and presence of MSH6 by immunohistochemistry, which indicates that the disease phenotype may be due to the MLH1 epigenetic change (PMID: 15354210). 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.
CSER _CC_NCGL, University of Washington	RCV000074941	SCV000503524	uncertain significance	Lynch syndrome	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 75 year male with a history of over 30 colon polyps and a family history of colon cancer.