Submissions for variant NM_000179.3(MSH6):c.3261dup (p.Phe1088fs)

dbSNP: rs267608078

Total submissions: 40

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074831	SCV000108042	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Eurofins Ntd Llc (ga)	RCV000078312	SCV000110155	pathogenic	not provided	2014-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000078312	SCV000149321	pathogenic	not provided	2020-12-01	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 Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Hampel 2008, Sjursen 2010, Terui 2013, Kumamoto 2015, Rubio 2016, Lee 2017, Suzuki 2017, Tian 2019) Observed in the homozygous and compound heterozygous state in patients with constitutional mismatch repair deficiency in published literature (Ilencikova 2011, Ling 2018) Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database Not observed at a significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 32068069, 32029870, 32658311, 32832836, 31447099, 32060697, 18809606, 20587412, 24100870, 26249337, 27398995, 28523262, 28258479, 31054147, 30147880, 21674763, 29945567, 31297992, 19526325, 30322717, 23757202, 28481244, 28514183, 28332257, 28502729, 26681312, 24068316, 26318770, 27978560, 27446556, 25980754, 24689082, 9307272, 25117503, 28724667, 28944238, 28491141, 28195393, 20028993, 20045164, 25194673, 25110875, 26845104, 17117178, 12658575, 15837969, 18301448, 9929971, 15365995, 15483016, 16807412, 17453009, 20487569)
Ambry Genetics	RCV000115412	SCV000185790	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-31	criteria provided, single submitter	clinical testing	The c.3261dupC (p.F1088Lfs*5) alteration, located in coding exon 5 of the MSH6 gene, consists of a duplication of C at position 3261, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the CC allele has an overall frequency of 0.006% (17/280876) total alleles studied. The highest observed frequency was 0.028% (2/7178) of Other alleles. This well-characterized mutation has been reported in multiple individuals and families with Lynch syndrome-associated cancers (Akiyama, 1997; Shin, 1999; Plaschke, 2004; Barnetson, 2006; Kets, 2006; Overbeek, 2007; Talseth-Palmer, 2010; Sjursen, 2010; Rosty, 2014). Based on the available evidence, this alteration is classified as pathogenic.
Invitae	RCV000524166	SCV000255263	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1088Leufs*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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 9307272, 9929971, 12658575, 15483016, 15837969, 16807412, 17117178, 17453009, 18301448, 24100870, 24689082, 25117503, 26318770). ClinVar contains an entry for this variant (Variation ID: 89364). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000078312	SCV000257248	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	PP1, PP4, PP5, PS4_moderate, PVS1
University of Washington Department of Laboratory Medicine, University of Washington	RCV000074831	SCV000266095	pathogenic	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000410401	SCV000489547	pathogenic	Lynch syndrome 5	2016-10-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115412	SCV000690338	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 5 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 detected in individuals and families affected with Lynch syndrome-associated cancer (PMID: 9307272, 9929971, 12658575, 15837969, 16807412, 17117178, 18301448, 24068316, 24100870, 25117503, 25110875, 25980754, 26681312, 28481244), as well as prostate or breast cancer (PMID: 25117503, 26681312). This variant also has been detected in homozygous and compound heterozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 21674763, 24068316, 30147880). This variant has been identified in 17/280876 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	RCV000074831	SCV000695854	likely pathogenic	Lynch syndrome	2016-08-01	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3261dupC (p.Phe1088Leufs) variant is located in exon 5 and results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 211/120336 (1/570), which is approximately 12 times the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7031. The high prevalence of the variant in controls can be explained by possibility of sequencing error, although the low penetrance is possibility too. The reason for low penetrance could be the existence of alternative splice acceptor site 7bp downstream of duplicated base, which can result in alternative protein lacking 32 amino acids. The variant of interest has been reported in multiple affected individuals with varying phenotypes, Lynch syndrome, atypical HNPCC, HNPCC (fulfilling either Bethesda or Amsterdam criteria), along with a family that had three homozygous children diagnosed with constitutional mismatch repair deficiency syndrome. In addition, one family (Palmer_2010) did indicate a lack of co-segregation with disease, along with another study, Yurgelun_2015 indicating the variant to have co-occurred with another pathogenic STK11 variant, c.375-1C>T. While other publications did indicate the variant segregated with disease (Akiyama_1997 and Ollikinen_2005). Furthermore, multiple reputable databases/clinical laboratories and publications cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074831	SCV000711433	pathogenic	Lynch syndrome	2022-01-20	criteria provided, single submitter	clinical testing	The p.Phe1088LeufsX5 variant in MSH6 has been reported in > 20 individuals with MSH6-associated cancers and segregated with disease in >3 affected relatives from 2 families (Akiyama 1997 PMID: 9307272, Plaschke 2004 PMID: 15483016, Ollikainen 2005 PMID: 15837969, Barnetson 2006 PMID: 16807412, Kets 2006 PMID: 17117178, Overbeek 2007 PMID: 17453009, Steinke 2008 PMID: 18301448, Sjursen 2010 PMID: 20587412, Bonadona 2011 PMID: 21642682, Terui 2013 PMID: 24100870, Hansen 2014 PMID: 24689082, Rosty 2014 PMID: 25117503, Susswein 2015 PMID: 26681312). Tumors sampled from some of these individuals lacked MSH6 expression (Ollikainen 2005 PMID: 15837969, Sjursen 2010 PMID: 20587412, Terui 2013 PMID: 24100870, Rosty 2014 PMID: 25117503). Additionally, this variant has been reported in the compound heterozygous state in 1 individual with constitutional mismatch repair deficiency (CMMRD) and family history of MSH6-associated cancers (Bougeard 2014 PMID: 24068316, Lavoine 2015 PMID: 26318770). This variant has also been identified in 0.009% (6/67594) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of MSH6-associated cancers in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 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 Lynch syndrome. In addition, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108042.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Supporting, PS4, PVS1, PS3.
GeneKor MSA	RCV000115412	SCV000821740	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variation is an insertion of 1 nucleotide in exon 5 of the MSH6 mRNA (c.3261dupC), causing a frameshift at codon 1088. This creates a premature translation stop signal 5 amino acid residues later- p.(Phe1088Leufs*5) 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 the literature in individuals with Lynch syndrome, colorectal, endometrial and prostate cancer (PMID: 9307272, PMID: 15483016, PMID: 26318770, PMID: 16807412, PMID: 24100870, (PMID: 25117503 PMID: 15837969). The mutation database ClinVar contains entries for this variant (Variation ID: 89364/).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000410401	SCV000840011	pathogenic	Lynch syndrome 5	2017-07-31	criteria provided, single submitter	clinical testing	This c.3261dupC variant has been reported in multiple individuals with Lynch Syndrome (PMID9929971, 15483016, 26318770), 3 additional patients with colon cancer (PMID17117178, 16807412, 24100870) and 5 more patients with endometrial cancer including 3 from the same family showing co-segregation from one generation to the next (PMID1711717, PMID17453009, PMID15837969). This variant is predicted to cause a frameshift and, and create a premature stop codon. Based upon the above evidence, this c.3261_3262insC variant in the MSH6 gene is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078312	SCV000888268	pathogenic	not provided	2020-01-10	criteria provided, single submitter	clinical testing	The MSH6 c.3261dup (p.Phe1088Leufs*5) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.00012 (3/24758 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals and families with Lynch syndrome-related cancers (PMIDs: 18301448 (2008), 20487569 (2010), 24100870 (2013), 24689082 (2014), 25980754 (2015), 28481244 (2017)). Based on the available information, this variant is classified as pathogenic.
Mendelics	RCV000410401	SCV001135836	pathogenic	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078312	SCV001250451	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PP1:Strong, PS4
Division of Medical Genetics, University of Washington	RCV000410401	SCV001424780	pathogenic	Lynch syndrome 5	2019-03-04	criteria provided, single submitter	clinical testing	The c.3261dupC variant is a known pathogenic variant in the MSH6 gene. This variant results in the substitution of a leucine for a phenylalanine at codon 1088 and a premature stop codon five residues downstream. The MSH6 c.3261dupC variant has been reported in a number of individuals with Lynch syndrome-associated cancers (Sjursen 2010, Terui 2013, McCarthy 2018). In addition, this variant has been reported in the homozygous state in three children from a consanguineous family that all had constitutional mismatch repair deficiency (Ilencikova 2011). Therefore, we interpret c.3261dupC as a pathogenic variant.
Johns Hopkins Genomics, Johns Hopkins University	RCV000410401	SCV001425317	pathogenic	Lynch syndrome 5	2020-04-29	criteria provided, single submitter	clinical testing	The MSH6 gene encodes a component of the DNA mismatch repair (MMR) system. The c.3261dupC variant in MSH6 has been reported in multiple individuals with Lynch Syndrome, an inherited condition that increases the risk of colorectal, endometrial and other cancers. It results in a premature stop codon in exon 5 likely leading to nonsense-mediated decay and lack of protein production. This variant is rare in a large population database (17/280876 total alleles, 0.0061%, no homozygotes) and has been reported in ClinVar. We consider this variant to be pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000078312	SCV001450264	pathogenic	not provided	2014-12-12	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000078312	SCV001480052	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000078312	SCV002017586	pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115412	SCV002528000	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	curation
DASA	RCV000410401	SCV002567975	pathogenic	Lynch syndrome 5	2022-08-10	criteria provided, single submitter	clinical testing	The c.3261dup;p.(Phe1088Leufs*5) is a null frameshift variant (NMD) in the MSH6 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 89364; PMID: 28466842; 28523262; 28502729; 32660107; 30387329; 32449172) -PS4. The variant is present at low allele frequencies population databases (rs267608078 – gnomAD 0.0005985%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting.The p.(Phe1088Leufs*5) was detected in trans with a pathogenic variant (PMID: 26318770) - PM3_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000410401	SCV002762825	pathogenic	Lynch syndrome 5	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_STR, BS1
Institute of Human Genetics, University of Leipzig Medical Center	RCV000410401	SCV002765105	likely pathogenic	Lynch syndrome 5	2022-12-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504982	SCV002813958	pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-04-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149722	SCV003838325	pathogenic	Breast and/or ovarian cancer	2022-06-27	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003315226	SCV004014869	pathogenic	MSH6-related disorder		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 5 of 10 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in MSH6 is an established mechanism of disease (PMID: 20301390, 18269114). This variant has been previously reported as a homozygous and compound heterozygous change in patients with constitutional mismatch repair deficiency syndrome and as a heterozygous change in patients with Lynch syndrome-associated cancers (PMID: 30147880, 26318770, 21674763, 28481244, 28523262). The c.3261dup (p.Phe1088LeufsTer5) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (17/280876) and thus is presumed to be rare. However, quality metrics indicate the frequency data for this variant in the population databases is considered unreliable in the gnomAD database. Based on the available evidence, c.3261dup (p.Phe1088LeufsTer5) is classified as Pathogenic.
Myriad Genetics, Inc.	RCV000410401	SCV004018950	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000410401	SCV004171404	pathogenic	Lynch syndrome 5	2023-11-13	criteria provided, single submitter	clinical testing	The MSH6 c.3261dup (p.Phe1088Leufs*5) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in the heterozygous state in individuals with Lynch syndrome as well as in the homozygous and compound heterozygous state in individuals with constitutional mismatch repair deficiency (PMID: 15837969, 24100870, 28491141, 29442399, 30147880, 33924881, 34738371, internal data). In summary, this variant meets criteria to be classified as pathogenic.
Baylor Genetics	RCV003128137	SCV004197683	pathogenic	Endometrial carcinoma	2023-09-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074831	SCV004835020	pathogenic	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	The c.3261dup (p.Phe1088Leufs*5) variant in the MSH6 gene is located on the exon 5 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Phe1088Leufs*5), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancers (PMID: 32660107, 34848827, 36387226, 30387329, 30147880, 32664968, 31845022, 31857677). The variant has been also reported in individuals with constitutional mismatch repair-deficiency syndrome in homozygous or compound heterozygous states (PMIS: 21674763, 24068316). Loss-of-function variants in MSH6 are known to be pathogenic and frameshift/truncating variants located downstream to this position have been reported in individuals with Lynch syndrome-associated cancers (PMID: 20028993, 18269114). This variant is reported in ClinVar as pathogenic (ID: 89364) and reviewed by expert panel. The variant is rare in general population according to gnomAD (17/280876). Therefore, the c.3261dup (p.Phe1088Leufs*5) variant of MSH6 has been classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074831	SCV000592631	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Phe1088LeufsX5 duplication variant was identified in 6 of 4432 proband chromosomes (frequency: 0.001) from individuals with suspected Lynch syndrome (phenotype of colorectal or endometrial cancer) (Kets 2006, Ollikainen 2005, Plaschke 2004). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1088 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function of the MSH6 gene is an established disease mechanism in Lynch Syndrome. The p.Phe1088LeufsX5 variant was shown to co-segregate with late-onset endometrial cancer in one family, with 6 members affected across 3 generations (Ollikainen 2005). In addition, the tumours from three individuals in this family, and the tumours from three other individuals positive for this variant (Kets 2006, Plaschke 2004) were deficient for MSH6 protein by IHC. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249970	SCV001423984	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000078312	SCV001905889	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078312	SCV001973540	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162477	SCV002758270	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
CZECANCA consortium	RCV003128137	SCV003804334	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000078312	SCV003839750	pathogenic	not provided	2022-10-02	no assertion criteria provided	clinical testing	DNA sequence analysis of the MSH6 gene demonstrated a 1 base pair duplication in exon 5, c.3261dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 5 amino acids downstream of the change, p.Phe1088Leufs*5. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MSH6 protein with potentially abnormal function. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in the gnomAD population database at a frequency of 0.012% in the African subpopulation (dbSNP rs1361078163), however this data is not considered reliable, as metrics indicate poor data quality at this position in the gnomAD database. This pathogenic sequence change has previously been described in individuals with Lynch syndrome (PMID: 9929971, 15483016, 26318770)).
deCODE genetics, Amgen	RCV000410401	SCV004022210	pathogenic	Lynch syndrome 5	2023-07-21	no assertion criteria provided	research	The variant NM_000179.3:c.3261dup (chr2:47803500) in MSH6 was detected in 5 heterozygotes out of 58K WGS Icelanders (MAF= 0,004%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PP5_Strong) this variant classifies as pathogenic.