VCV000089364.99 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

45 submissions

45 submitters

12 conditions

Reviewed by expert panel

Pathogenic

Sep 2013 by International …

for Lynch Syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 89364 Accession: VCV000089364.99

Type and length

Duplication, 1 bp

Location

Cytogenetic: 2p16.3 2: 47803500-47803501 (GRCh38) [ NCBI UCSC ] 2: 48030639-48030640 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 24, 2015	Oct 20, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.3261dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Phe1088fs	frameshift
NM_000179.3:c.3261dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000179.2:c.3261dupC
NM_001281492.2:c.2871dup	NP_001268421.1:p.Phe958fs	frameshift
NM_001281493.2:c.2355dup	NP_001268422.1:p.Phe786fs	frameshift
NM_001281494.2:c.2355dup	NP_001268423.1:p.Phe786fs	frameshift
NC_000002.12:g.47803508dup
NC_000002.11:g.48030647dup
NG_007111.1:g.25362dup
LRG_219:g.25362dup

... more HGVS ... less HGVS

Protein change

F1088fs, F786fs, F958fs

Other names

p.Phe1088LeufsX5

Canonical SPDI

NC_000002.12:47803500:CCCCCCCC:CCCCCCCCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA012175 dbSNP: rs267608078 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MSH6		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	9159	9475

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Lynch syndrome	Pathogenic (6)	reviewed by expert panel	Sep 5, 2013	RCV000074831.21
not provided	Pathogenic (13)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000078312.52
Hereditary cancer-predisposing syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000115412.26
Lynch syndrome 5	Pathogenic/Likely pathogenic (12)	criteria provided, multiple submitters, no conflicts	Oct 15, 2024	RCV000410401.19
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV000524166.17
Lynch-like syndrome	Pathogenic (1)	no assertion criteria provided	Jul 1, 2019	RCV001249970.8
MSH6-related disorder	Pathogenic (2)	criteria provided, single submitter	-	RCV003315226.9
Endometrial carcinoma Lynch syndrome 5 Mismatch repair cancer syndrome 3	Pathogenic (1)	criteria provided, single submitter	Apr 19, 2022	RCV002504982.8
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162477.8
Endometrial carcinoma	Pathogenic (2)	criteria provided, single submitter	Mar 25, 2024	RCV003128137.10
Breast and/or ovarian cancer	Pathogenic (1)	criteria provided, single submitter	Jun 27, 2022	RCV003149722.9
Inherited MMR deficiency (Lynch syndrome)	Pathogenic (1)	criteria provided, single submitter	Apr 17, 2024	RCV004584186.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 05, 2013)	reviewed by expert panel (Guidelines v1.9) Method: research	Lynch Syndrome Affected status: unknown Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000108042.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comment: Coding sequence variation resulting in a stop codon
Pathogenic (Jul 31, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000840011.1 First in ClinVar: Jan 06, 2017 Last updated: Jan 06, 2017	Comment: 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 … (more) 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. (less)
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135836.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821740.2 First in ClinVar: Oct 10, 2018 Last updated: Mar 25, 2020	Comment: 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 … (more) 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/). (less)
Pathogenic (Dec 12, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450264.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 4
Pathogenic (Feb 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001480052.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Clinical Features: Colon cancer (present) Sex: female
Likely pathogenic (Dec 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002765105.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Lynch syndrome 5 Affected status: no Allele origin: germline	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV002762825.2 First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023	Comment: PVS1, PS4_STR, BS1
Pathogenic (Jun 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838325.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MSH6-related disorders Affected status: unknown Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004014869.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257248.3 First in ClinVar: Nov 20, 2015 Last updated: Jan 26, 2024	Publications: PubMed (8) PubMed: 15483016‚ 15837969‚ 16807412‚ 17117178‚ 18809606‚ 20587412‚ 24100870‚ 9307272 Comment: PP1, PP4, PP5, PS4_moderate, PVS1 Number of individuals with the variant: 8
Pathogenic (Dec 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000690338.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (16) PubMed: 9307272‚ 9929971‚ 12658575‚ 15837969‚ 16807412‚ 17117178‚ 18301448‚ 21674763‚ 24068316‚ 24100870‚ 25110875‚ 25117503‚ 25980754‚ 26681312‚ 28481244‚ 30147880 Comment: 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 … (more) 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. (less)
Pathogenic (Nov 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004835020.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (10) PubMed: 18269114‚ 20028993‚ 30147880‚ 30387329‚ 31845022‚ 31857677‚ 32660107‚ 32664968‚ 34848827‚ 36387226 Comment: The c.3261dup (p.Phe1088Leufs5) variant in the MSH6 gene is located on the exon 5 and is predicted to cause reading frame shift that introduces a … (more) The c.3261dup (p.Phe1088Leufs5) 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.Phe1088Leufs5), 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.Phe1088Leufs5) variant of MSH6 has been classified as pathogenic. (less) Number of individuals with the variant: 8
Pathogenic (Jan 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711433.3 First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024	Publications: PubMed (16) PubMed: 17453009‚ 20587412‚ 18301448‚ 9307272‚ 16807412‚ 21642682‚ 24689082‚ 28195393‚ 17117178‚ 26318770‚ 15837969‚ 15483016‚ 25117503‚ 26681312‚ 24100870‚ 24068316 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004197683.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Apr 17, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Inherited MMR deficiency (Lynch syndrome) Affected status: yes Allele origin: germline	Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005068353.1 First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024	Comment: PVS1,PS4_Very Strong,PP4_Very Strong
Pathogenic (Oct 15, 2024)	criteria provided, single submitter (Hauer et al. (Genet Med. 2018)) Method: clinical testing	Lynch syndrome 5 (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Accession: SCV005374601.1 First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024	Comment: This variant has been identified by standard clinical testing. female patient with bilateral breast cancer, endometrial cancer and ovarian cancer Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1 Number of individuals with the variant: 1
Pathogenic (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Hereditary nonpolyposis colon cancer Affected status: yes Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266095.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Number of individuals with the variant: 1 Clinical Features: colon cancer (present) Age: 50-59 years
Pathogenic (Jan 24, 2014)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110155.5 First in ClinVar: Jan 23, 2014 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 23757202 Number of individuals with the variant: 3 Sex: mixed
Likely pathogenic (Aug 01, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary nonpolyposis colon cancer Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695854.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (17) PubMed: 15837969‚ 16807412‚ 15483016‚ 20028993‚ 18809606‚ 21674763‚ 17117178‚ 20487569‚ 9307272‚ 21642682‚ 25194673‚ 25980754‚ 20045164‚ 26845104‚ 25110875‚ 25117503‚ 9929971 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: no Allele origin: germline	Division of Medical Genetics, University of Washington Study: CSER_CHARM Accession: SCV001424780.1 First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020	Comment: 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 … (more) 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. (less) Indication for testing: family history of colorectal cancer
Pathogenic (Apr 29, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001425317.1 First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020	Publications: PubMed (3) PubMed: 24362816‚ 27854360‚ 32141610 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 01, 2020)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149321.12 First in ClinVar: May 17, 2014 Last updated: Jun 26, 2021	Comment: 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 … (more) 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) (less)
Pathogenic (Nov 17, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002528000.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MSH6 c.3261dupC (p.F1088LfsX5) variant has been reported as compound heterozygous in several individuals with constitutional mismatch repair deficiency syndrome (PMID: 26318770, 30147880). The variant … (more) The MSH6 c.3261dupC (p.F1088LfsX5) variant has been reported as compound heterozygous in several individuals with constitutional mismatch repair deficiency syndrome (PMID: 26318770, 30147880). The variant has also been reported in heterozygosity in numerous individuals with Lynch syndrome related cancers, such as colorectal, uterine, endometrial, gastric or breast cancer (PMID: 32660107, 32060697, 31783044, 31845022, among others). Tumors found in these patients exhibit loss of MSH6 protein expression (PMID: 32660107, 31783044, 26318770, among others). This variant was identified in several family/families, where it was found to segregate with the phenotype (PMID: 15837969, 9307272). It is also known as c.3254dupC (p.T1085fs) in the literature. This variant causes a frameshift at amino acid 1088 that results in premature termination 5 amino acids downstream. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). Loss of function variants in MSH6 are known to be pathogenic (PMID: 20301390). This variant was observed in 3/24758 chromosomes in the African population according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654), and has been reported in ClinVar (Variation ID: 89364). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (9) PubMed: 26318770‚ 30147880‚ 32660107‚ 32060697‚ 31783044‚ 31845022‚ 15837969‚ 9307272‚ 20301390
Pathogenic (Aug 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: germline	DASA Accession: SCV002567975.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022	Publications: PubMed (7) PubMed: 28466842‚ 28523262‚ 28502729‚ 32660107‚ 30387329‚ 32449172‚ 26318770 Comment: The c.3261dup;p.(Phe1088Leufs5) is a null frameshift variant (NMD) in the MSH6 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a … (more) The c.3261dup;p.(Phe1088Leufs5) 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. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Argentina
Pathogenic (Oct 26, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000489547.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022	Publications: PubMed (2) PubMed: 9929971‚ 18301448
Pathogenic (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Lynch syndrome 5 Mismatch repair cancer syndrome 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813958.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Mar 29, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018950.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Nov 13, 2023)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV004171404.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Comment: The MSH6 c.3261dup (p.Phe1088Leufs5) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to … (more) The MSH6 c.3261dup (p.Phe1088Leufs5) 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. (less)
Pathogenic (Jan 10, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888268.3 First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024	Publications: PubMed (39) PubMed: 18301448‚ 17453009‚ 17117178‚ 17082796‚ 16807412‚ 15837969‚ 15483016‚ 12658575‚ 24100870‚ 20487569‚ 25980754‚ 9307272‚ 26318770‚ 9929971‚ 24689082‚ 24362816‚ 18269114‚ 26681312‚ 28491141‚ 28523262‚ 28724667‚ 28944238‚ 29442399‚ 29945567‚ 30147880‚ 30322717‚ 30787465‚ 31054147‚ 31297992‚ 31447099‚ 32029870‚ 32060697‚ 32068069‚ 32658311‚ 32832836‚ 33087929‚ 34178123‚ 25117503‚ 28481244 Comment: The MSH6 c.3261dup (p.Phe1088Leufs5) variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. The frequency … (more) The MSH6 c.3261dup (p.Phe1088Leufs5) 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. (less)
Pathogenic (Apr 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017586.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000255263.12 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024	Publications: PubMed (16) PubMed: 28492532‚ 18269114‚ 24362816‚ 9307272‚ 9929971‚ 12658575‚ 15483016‚ 15837969‚ 16807412‚ 17117178‚ 17453009‚ 18301448‚ 24100870‚ 24689082‚ 25117503‚ 26318770 Comment: This sequence change creates a premature translational stop signal (p.Phe1088Leufs5) in the MSH6 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Phe1088Leufs5) 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. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000185790.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (10) PubMed: 9307272‚ 9929971‚ 15483016‚ 16807412‚ 17117178‚ 17453009‚ 20487569‚ 20587412‚ 25117503‚ 28481244 Comment: The c.3261dupC (p.F1088Lfs5) alteration, located in coding exon 5 of the MSH6 gene, consists of a duplication of C at position 3261, causing a translational … (more) The c.3261dupC (p.F1088Lfs5) 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. (less)
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005090497.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024
Pathogenic (Aug 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199213.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250451.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: MSH6: PVS1, PP1:Strong, PS4 Number of individuals with the variant: 7
Pathogenic (Aug 13, 2024)	no assertion criteria provided Method: clinical testing	MSH6-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362570.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MSH6 c.3261dupC variant is predicted to result in a frameshift and premature protein termination (p.Phe1088Leufs5). This variant (also described as 1087insC, c.3524dupC, and c.3261_3262insC) … (more) The MSH6 c.3261dupC variant is predicted to result in a frameshift and premature protein termination (p.Phe1088Leufs5). This variant (also described as 1087insC, c.3524dupC, and c.3261_3262insC) has been reported in multiple individuals with Lynch syndrome and Lynch-associated cancers (Akiyama et al. 1997. PubMed ID: 9307272; Table S1, Baglietto et al. 2010. PubMed ID: 20028993; eTable1, Bonadona et al. 2011. PubMed ID: 21642682; Table S1, DeRycke et al. 2017. PubMed ID: 28944238; Table S1, Carter et al. 2018. PubMed ID: 30322717; Table S3, Yang et al. 2021. PubMed ID: 34178123; Table S1, Gordhandas et al. 2023. PubMed ID: 36744932). It has also been observed in the compound heterozygous state in individuals with constitutional mismatch repair deficiency syndrome (CMMRD) (Lavoine et al. 2015. PubMed ID: 26318770; Ling et al. 2018. PubMed ID: 30147880). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has been interpreted as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89364/). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Jul 01, 2019)	no assertion criteria provided Method: clinical testing	Lynch-like syndrome Affected status: yes Allele origin: somatic	Constitutional Genetics Lab, Leon Berard Cancer Center Accession: SCV001423984.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Number of individuals with the variant: 4
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Lynch syndrome Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000592631.2 First in ClinVar: Oct 11, 2015 Last updated: Jul 06, 2020	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 3
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001905889.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973540.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758270.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
Pathogenic (Feb 21, 2023)	no assertion criteria provided Method: clinical testing	Endometrial carcinoma Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV003804334.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023	Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (Oct 02, 2022)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV003839750.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: 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 … (more) 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)). (less)
Pathogenic (Jul 21, 2023)	no assertion criteria provided Method: research	Lynch syndrome 5 Affected status: yes Allele origin: germline	deCODE genetics, Amgen Accession: SCV004022210.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 5 Ethnicity/Population group: Icelandic
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Comment:

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.

Comment:

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/).

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

The MSH6 c.3261dupC variant is predicted to result in a frameshift and premature protein termination (p.Phe1088Leufs*5). This variant (also described as 1087insC, c.3524dupC, and c.3261_3262insC) has been reported in multiple individuals with Lynch syndrome and Lynch-associated cancers (Akiyama et al. 1997. PubMed ID: 9307272; Table S1, Baglietto et al. 2010. PubMed ID: 20028993; eTable1, Bonadona et al. 2011. PubMed ID: 21642682; Table S1, DeRycke et al. 2017. PubMed ID: 28944238; Table S1, Carter et al. 2018. PubMed ID: 30322717; Table S3, Yang et al. 2021. PubMed ID: 34178123; Table S1, Gordhandas et al. 2023. PubMed ID: 36744932). It has also been observed in the compound heterozygous state in individuals with constitutional mismatch repair deficiency syndrome (CMMRD) (Lavoine et al. 2015. PubMed ID: 26318770; Ling et al. 2018. PubMed ID: 30147880). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has been interpreted as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89364/). Frameshift variants in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

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.

Comment:

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)).

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes.	Reitsam NG	Frontiers in oncology	2022	PMID: 36387226
Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors.	Kim H	Laboratory investigation; a journal of technical methods and pathology	2022	PMID: 34848827
Development and external validation of a novel nomogram for screening Chinese Lynch syndrome: based on a multicenter, population study.	Yang M	Therapeutic advances in medical oncology	2021	PMID: 34178123
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.	Akcay IM	International journal of cancer	2021	PMID: 32658311
Lynch Syndrome.	Adam MP	-	2021	PMID: 20301390
Exome sequencing and characterization of 49,960 individuals in the UK Biobank.	Van Hout CV	Nature	2020	PMID: 33087929
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.	Matejcic M	JCO precision oncology	2020	PMID: 32832836
Next generation sequencing to decipher concurrent loss of PMS2 and MSH6 in colorectal cancer.	Moreno E	Diagnostic pathology	2020	PMID: 32664968
Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results.	Olkinuora A	Cancers	2020	PMID: 32660107
Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors.	Salem ME	International journal of cancer	2020	PMID: 32449172
Molecular pathology of Lynch syndrome.	Cerretelli G	The Journal of pathology	2020	PMID: 32141610
Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel.	Kwong A	The Journal of molecular diagnostics : JMD	2020	PMID: 32068069
Mismatch repair gene pathogenic germline variants in a population-based cohort of breast cancer.	Nguyen-Dumont T	Familial cancer	2020	PMID: 32060697
Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors.	Hata C	Journal of human genetics	2020	PMID: 32029870
Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes.	Hechtman JF	Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc	2020	PMID: 31857677
Colorectal cancer in Lynch syndrome associated with PMS2 and MSH6 mutations.	Yılmaz A	International journal of colorectal disease	2020	PMID: 31845022
MSH6 immunohistochemical heterogeneity in colorectal cancer: comparative sequencing from different tumor areas.	Chen W	Human pathology	2020	PMID: 31783044
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
Comprehensive mismatch repair gene panel identifies variants in patients with Lynch-like syndrome.	Xavier A	Molecular genetics & genomic medicine	2019	PMID: 31297992
Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes.	Tian W	International journal of cancer	2019	PMID: 31054147
Toward automation of germline variant curation in clinical cancer genetics.	Ravichandran V	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30787465
Heterogenous loss of mismatch repair (MMR) protein expression: a challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation.	McCarthy AJ	The journal of pathology. Clinical research	2019	PMID: 30387329
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Rare compound heterozygous mutations in gene MSH6 cause constitutive mismatch repair deficiency syndrome.	Ling C	Clinical case reports	2018	PMID: 30147880
Pancreatic cancer as a sentinel for hereditary cancer predisposition.	Young EL	BMC cancer	2018	PMID: 29945567
Clinicopathologic characteristics of double primary endometrial and colorectal cancers in a single institution.	Lee HJ	The journal of obstetrics and gynaecology research	2018	PMID: 29442399
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.	DeRycke MS	Molecular genetics & genomic medicine	2017	PMID: 28944238
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
Case Report of Menopausal Woman Diagnosed with Endometrial Cancer after Colon Cancer with Germline Mutation in MSH6 in Korea.	Lee HJ	Journal of menopausal medicine	2017	PMID: 28523262
Improving Mutation Screening in Patients with Colorectal Cancer Predisposition Using Next-Generation Sequencing.	Rey JM	The Journal of molecular diagnostics : JMD	2017	PMID: 28502729
Universal molecular screening does not effectively detect Lynch syndrome in clinical practice.	Brennan B	Therapeutic advances in gastroenterology	2017	PMID: 28491141
Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome.	Liccardo R	International journal of molecular sciences	2017	PMID: 28481244
Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.	Haraldsdottir S	Nature communications	2017	PMID: 28466842
Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome.	Hansen MF	Clinical genetics	2017	PMID: 28195393
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.	Kalia SS	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27854360
Improving performance of multigene panels for genomic analysis of cancer predisposition.	Shirts BH	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26845104
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.	Lavoine N	Journal of medical genetics	2015	PMID: 26318770
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.	Yurgelun MB	Gastroenterology	2015	PMID: 25980754
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers.	Kang SY	International journal of cancer	2015	PMID: 25110875
Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.	Haraldsdottir S	Gastroenterology	2014	PMID: 25194673
High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry.	Rosty C	Familial cancer	2014	PMID: 25117503
A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes.	Hansen MF	Molecular genetics & genomic medicine	2014	PMID: 24689082
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.	Thompson BA	Nature genetics	2014	PMID: 24362816
Diversity of the clinical presentation of the MMR gene biallelic mutations.	Bougeard G	Familial cancer	2014	PMID: 24068316
Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients.	Terui H	Oncology reports	2013	PMID: 24100870
High-grade brain tumors in siblings with biallelic MSH6 mutations.	Ilencikova D	Pediatric blood & cancer	2011	PMID: 21674763
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.	Bonadona V	JAMA	2011	PMID: 21642682
Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.	Sjursen W	Journal of medical genetics	2010	PMID: 20587412
MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer.	Talseth-Palmer BA	Hereditary cancer in clinical practice	2010	PMID: 20487569
Taiwan hospital-based detection of Lynch syndrome distinguishes 2 types of microsatellite instabilities in colorectal cancers.	Chang SC	Surgery	2010	PMID: 20045164
Risks of Lynch syndrome cancers for MSH6 mutation carriers.	Baglietto L	Journal of the National Cancer Institute	2010	PMID: 20028993
Feasibility of screening for Lynch syndrome among patients with colorectal cancer.	Hampel H	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2008	PMID: 18809606
No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients.	Steinke V	European journal of human genetics : EJHG	2008	PMID: 18301448
Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.	Devlin LA	The Ulster medical journal	2008	PMID: 18269114
Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer.	Overbeek LI	British journal of cancer	2007	PMID: 17453009
Persistent mismatch repair deficiency following targeted correction of hMLH1.	Weiss MB	Cancer gene therapy	2007	PMID: 17082796
Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability.	Kets CM	British journal of cancer	2006	PMID: 17117178
Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.	Barnetson RA	The New England journal of medicine	2006	PMID: 16807412
Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome?	Ollikainen M	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2005	PMID: 15837969
Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.	Plaschke J	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2004	PMID: 15483016
Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene.	Wagner A	American journal of human genetics	2003	PMID: 12658575
Germline mutations in a polycytosine repeat of the hMSH6 gene in Korean hereditary nonpolyposis colorectal cancer.	Shin KH	Journal of human genetics	1999	PMID: 9929971
Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred.	Akiyama Y	Cancer research	1997	PMID: 9307272
http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.3261dup	-	-	-	-
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Text-mined citations for rs267608078 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267608078 ...