ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.383G>T (p.Arg128Leu) (rs63750143)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165162 SCV000215873 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000485426 SCV000571560 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.383G>T at the cDNA level, p.Arg128Leu (R128L) at the protein level, and results in the change of an Arginine to a Leucine (CGT>CTT). MSH6 Arg128Leu has been observed in at least one women with a MSI-H endometrial tumor where loss of MLH1 and retention of MSH2 and MSH6 was noted via IHC while subsequent MLH1 promoter hypermethylation was detected (Kariola 2004, Hampel 2006). While Kariola et al. (2004) suggests that this variant does not negatively impact MMR activity in an in vitro assay, Li et al. (2013) has found that the N-terminus, where MSH6 Arg128Leu is located, is not required for in vitro MMR activity but is critical for the MSH2-MSH6 heterodimer recruitment to chromatin in vivo; functional assays to assess chromatin recruitment have not, to our knowledge, been completed for this variant. MSH6 Arg128Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg128Leu occurs at a position that is not conserved and is located within the PWWP domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg128Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000545223 SCV000624931 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 128 of the MSH6 protein (p.Arg128Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) affected with endometrial cancer and colorectal cancer (PMID: 15354210, 28135145). ClinVar contains an entry for this variant (Variation ID: 89473). Experimental studies have shown that this variant does not affect interaction with MSH2 or mismatch repair (MMR) activity in vitro (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; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000165162 SCV001352506 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-17 criteria provided, single submitter clinical testing
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.

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