Submissions for variant NM_000179.3(MSH6):c.3514dup (p.Arg1172fs)

gnomAD frequency: 0.00001  dbSNP: rs63751327

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074872	SCV000108084	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000166347	SCV000217134	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	clinical testing	The c.3514dupA pathogenic mutation, located in coding exon 6 of the MSH6 gene, results from a duplication of A at nucleotide position 3514, causing a translational frameshift with a predicted alternate stop codon (p.R1172Kfs*5). This mutation has been identified in multiple families with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Overbeek LI et al. Br. J. Cancer. 2007 May;96:1605-12; Steinke V et al. Eur. J. Hum. Genet. 2008 May;16:587-92; Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83; van der Post RS et al. J. Med. Genet. 2010 Jul;47:464-70; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; Haraldsdottir S et al. Nat. Commun. 2017 May;8:14755). This alteration has also been detected in conjunction with another MSH6 mutation in 17-year-old patient with a clinical diagnosis of congenital mismatch repair deficiency syndrome (Soplepmann J et al. Acta Oncol. 2016 Dec;55:1503-1505). In addition to the clinical data presented in the literature, 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	RCV000627713	SCV000283809	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1172Lysfs*5) 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 present in population databases (rs63751327, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and urothelial, colorectal, bladder and ovarian cancer (PMID: 10508506, 18566915, 19130300, 20587412, 20591884, 20682701, 24728189). This variant is also known as 1172insA or c.3514_3515insA. ClinVar contains an entry for this variant (Variation ID: 89404). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000409599	SCV000488032	pathogenic	Lynch syndrome 5	2015-12-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202194	SCV000888277	pathogenic	not provided	2020-02-03	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000166347	SCV000905457	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide 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-associated cancer (PMID: 10508506, 18566915, 19130300, 20587412, 20591884, 20682701, 24728189, 28466842). This variant has been identified in 3/282730 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074872	SCV000917779	pathogenic	Lynch syndrome	2018-10-19	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3514dupA (p.Arg1172LysfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.1e-05 in 277060 control chromosomes (gnomAD). c.3514dupA has been reported in the literature in multiple individuals affected with Lynch Syndrome or related tumor phenotypes (Nilbert 2009, Schofield 2009, Sjursen 2010, Steinke2008, Wijnen 1999, Plaschke 2004, Haraldsdottir 2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000202194	SCV001168605	pathogenic	not provided	2018-12-19	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH6 is denoted c.3514dupA at the cDNA level and p.Arg1172LysfsX5 (R1172KfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TGAT[dupA]GAGT. The duplication causes a frameshift which changes an Arginine to a Lysine at codon 1172, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3514dupA, also reported as MSH6 3514insA, has been reported in individuals meeting Bethesda guidelines and Amsterdam criteria for Lynch syndrome. (Plaschke 2004 , Overbeek 2007, Nilbert 2009, Sjursen 2010, van der Post 2010, Haraldsdottir 2017). This variant was also observed in the compound heterozygous state in an individual with constitutional mismatch repair deficiency (CMMR-D) syndrome (Soplepmann 2016). We consider this variant to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000202194	SCV001746353	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000202194	SCV002010092	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409599	SCV004018983	pathogenic	Lynch syndrome 5	2023-03-29	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	RCV003460686	SCV004197690	pathogenic	Endometrial carcinoma	2023-09-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074872	SCV004835080	pathogenic	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide 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-associated cancer (PMID: 10508506, 18566915, 19130300, 20587412, 20591884, 20682701, 24728189, 28466842). This variant has been identified in 3/282730 chromosomes 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074872	SCV004848300	pathogenic	Lynch syndrome	2021-10-28	criteria provided, single submitter	clinical testing	The p.Arg1172LysfsX5 variant in MSH6 has been previously reported in at least 14 individuals with Lynch syndrome or associated cancers, and segregated with disease in 3 affected relatives from 1 family (Wijnen 1999 PMID: 10508506, Plaschke 2004 PMID: 15483016, Jenkins 2006 PMID: 16616355, Overbeek 2007 PMID: 17453009, Steinke 2008 PMID: 18301448, Nilbert 2009 PMID: 19130300, van der Post 2010 PMID: 20591884, Sjursen 2010 PMID: 20587412, Woods 2010 PMID: 20682701, Song 2014 PMID: 24728189, Haraldsdottir 2017 PMID: 28466842, Jiang 2019 PMID: 30521064) and in 1 individual with constitutive mismatch repair deficiency in the compound heterozygous state (Soplepmann 2016 PMID: 27723366). It has been identified in 0.003% (1/35414) of Latino and in 0.002% (2/129076) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1172 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. Additionally, this variant was classified as Pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108084.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2_Supporting, PM3, PP1.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202194	SCV000257260	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353417	SCV000592646	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg1172LysfsX5 duplication variant was identified in 5 of 5380 proband chromosomes (frequency: 0.001) from individuals with colorectal cancer or other cancers associated with Lynch syndrome (Nilbert 2009, Overbeek 2007, Plaschke 2004, Schofield 2009, Wijnen 1999). This variant was also identified in dbSNP (ID: rs63751327), HGMD, UMD (7X), “Mismatch Repair Genes Variant Database”, and the “InSiGHT Colon Cancer Database”. The p.Arg1172LysfsX5 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1172 and leads to a premature stop codon at position 1176. This alteration is then predicted to result in a truncated or absent protein and loss of function. Two studies demonstrated a loss of MSH6 expression in tumours with the variant (Schofield 2009, You 2010), and loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory for Genotyping Development, RIKEN	RCV003162478	SCV002758272	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research