Submissions for variant NM_000179.3(MSH6):c.3516_3517del (p.Arg1172fs)

dbSNP: rs398123232

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078316	SCV000110160	pathogenic	not provided	2013-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162479	SCV000212852	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-31	criteria provided, single submitter	clinical testing	The c.3516_3517delAG pathogenic mutation, located in coding exon 6 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3516 to 3517, causing a translational frameshift with a predicted alternate stop codon (p.R1172Sfs*4). This mutation has previously been identified in a family with HNPCC/Lynch syndrome (Baglietto, L et al. J Natl Cancer Inst. 2010 Feb 3;102(3):193-201). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000200371	SCV000255264	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1172Serfs*4) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is also known as c.3516_3517delAG (p.R1172fs). ClinVar contains an entry for this variant (Variation ID: 92578). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000078316	SCV000568727	pathogenic	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Baglietto et al., 2010; Graham et al., 2015; Yurgelun et al., 2015; Pearlman et al., 2019); This variant is associated with the following publications: (PMID: 31491536, 30877237, 20028993, 25980754, 26099011, 31159747, 30787465, 28888541)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078316	SCV000601577	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome (PMID: 25980754 (2015)), colorectal cancer (PMID: 30877237 (2019)), ovarian cancer (PMID: 28888541 (2017)), and breast and/or ovarian cancer (PMID: 31159747 (2019)). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000162479	SCV000821741	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This mutation is a deletion of two nucleotides from exon 6 of the MSH6 mRNA (c.3516_3517delAG), causing a frameshift at codon 1172. This creates a premature translational stop signal after 4 amino acid residues (p.Arg1172Serfs*4) and is expected to result in an absent or disrupted protein product. Truncating variants in MSH6 are known to be pathogenic. This mutation has been reported in association with Lynch syndrome (PMID: 20028993).The mutation database ClinVar contains entries for this variant (Variation ID: 92578).
Color Diagnostics, LLC DBA Color Health	RCV000162479	SCV001340972	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 6 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 25980754, 26099011) and colorectal cancer (PMID: 20028993). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000078316	SCV001713988	pathogenic	not provided	2023-01-27	criteria provided, single submitter	clinical testing	PP4, PM2, PS4_moderate, PVS1
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001814046	SCV002061822	pathogenic	Lynch syndrome 5	2021-12-31	criteria provided, single submitter	clinical testing	PVS1, PM2, PS4_Moderate
Myriad Genetics, Inc.	RCV001814046	SCV004188252	pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003466971	SCV004197634	pathogenic	Endometrial carcinoma	2023-10-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997195	SCV004835082	pathogenic	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 6 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 25980754, 26099011) and colorectal cancer (PMID: 20028993). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.