ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.2251delinsAAAA (p.Gly751delinsLysSer) (rs63751408)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130652 SCV000185537 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Insufficient evidence
Invitae RCV000074770 SCV000283759 uncertain significance Lynch syndrome 2017-01-11 criteria provided, single submitter clinical testing This sequence change deletes one nucleotide and inserts 4 nucleotides in exon 4 of the MSH6 mRNA (c.2641delGinsAAAA). This leads to the replacement of glycine with lysine and the insertion of an additional serine amino acid residue in the MSH6 protein (p.Gly881delinsLysSer) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with endometrial cancer (PMID: 15354210, 16885385). ClinVar contains an entry for this variant (Variation ID: 89305). Experimental studies have shown that this variant does not impact MSH6 mismatch repair activity or its ability to bind MSH2 (PMID: 15354210). In summary, this variant is a rare in-frame insertion that has been shown to not affect protein function in vitro. It has been reported in an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000411650 SCV000487931 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000657069 SCV000568108 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2641delGinsAAAA at the cDNA level and p.Gly881delinsLysSer (G881delinsKS) at the protein level. The surrounding sequence is TGAT[delG][insAAAA]GTTT. This in-frame deletion and insertion results in the deletion of a Glycine residue and an insertion of Lysine and Serine residues. This variant has been reported at least once, in an individual with endometrial cancer at age 83 with no family history of Lynch-syndrome related cancers (Hampel 2006). Tumors studies were reported to exhibit microsatellite instability (MSI) with loss of MLH1 on immunohistochemistry (IHC), intact expression of MSH2 and MSH6, and MLH1 promoter methylation. Functional studies have shown that MSH6 Gly881delinsLysSer was able to dimerize with MSH2 and had mismatch repair (MMR) activity similar to wild type MSH6 cells in an in vitro MMR assay (Kariola 2004). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as an uncertain variant based on insufficient evidence (Thompson 2014). This variant was not observed in large population cohorts (Lek 2016). This variant is located in the lever domain (Warren 2007, Kansikas 2011). Based on currently available evidence, , it is unclear whether MSH6 c.2641delGinsAAAA is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485683 SCV000601535 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing
Color RCV000130652 SCV000685305 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing
Invitae RCV000630063 SCV000751019 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-05 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide and inserts 4 nucleotides in exon 4 of the MSH6 mRNA (c.2641delinsAAAA). This leads to the replacement of glycine with lysine and the insertion of an additional serine amino acid residue in the MSH6 protein (p.Gly881delinsLysSer) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with endometrial cancer (PMID: 15354210). ClinVar contains an entry for this variant (Variation ID: 89305). Experimental studies have shown that this variant does not impact MSH6 mismatch repair activity, protein expression or its ability to bind MSH2 (PMID: 15354210, 21120944). 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.

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