Submissions for variant NM_000179.3(MSH6):c.2641delinsAAAA (p.Gly881delinsLysSer)

dbSNP: rs63751408

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130652	SCV000185537	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-10	criteria provided, single submitter	clinical testing	The c.2641delGinsAAAA variant (also known as p.G881delinsKS), located in coding exon 4 of the MSH6 gene, results from an in-frame deletion of one nucleotide and insertion of four nucleotides at position 2641. This results in the deletion of a glycine residue at codon 881 and insertion of a lysine and serine residue. This amino acid position is poorly conserved in available vertebrate species. This alteration has been reported in an individual diagnosed with endometrial cancer at age 83 whose tumor displayed high microsatellite instability (MSI-H) with absent MLH1 protein expression and positive MSH2/MSH6 protein expression by immunohistochemistry (IHC); MLH1 promoter methylation studies also showed hypermethylation (Kariola R et al. Br J Cancer. 2004 Oct 4;91(7):1287-92; Hampel H et al. Cancer Res. 2006 Aug;66:7810-7). In a functional study, this variant demonstrated relative mismatch repair activity similar to wild type MSH6 in an in vitro complementation assay and interaction with MSH2 remained intact (Kariola R et al. Br J Cancer. 2004 Oct 4;91(7):1287-92). In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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	Lynch syndrome 5	2015-12-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000657069	SCV000568108	uncertain significance	not provided	2021-01-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: ability to dimerize with MSH2 and mismatch repair (MMR) activity similar to wild type in an in vitro MMR assay (Kariola 2004); In-frame deletion of 1 amino acid and insertion of 2 amino acids in a non-repeat region; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Observed in individual with a personal history of endometrial cancer (Hampel 2006); This variant is associated with the following publications: (PMID: 16885385, 15354210, 21120944, 28873162)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657069	SCV000601535	uncertain significance	not provided	2021-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130652	SCV000685305	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This variant causes the deletion of a glycine and insertion of lysine and serine at codon 881 in the MSH6 protein. Functional studies have shown that this variant does not impact MSH6 mismatch repair activity, protein expression, or binding to MSH2 (PMID: 15354210, 21120944). This variant has been reported in an individual affected with endometrial cancer (PMID: 15354210, 16885385) 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.
Myriad Genetics, Inc.	RCV000411650	SCV004019068	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.
Baylor Genetics	RCV003460670	SCV004197580	uncertain significance	Endometrial carcinoma	2023-10-24	criteria provided, single submitter	clinical testing
Invitae	RCV003764749	SCV004670061	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-23	criteria provided, single submitter	clinical testing	This variant, c.2641delinsAAAA , is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the MSH6 protein (p.Gly881delinsLysSer). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with endometrial cancer (PMID: 15354210). ClinVar contains an entry for this variant (Variation ID: 89305). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant does not substantially affect MSH6 function (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.