VCV000042472.52 - ClinVar

NM_000179.3(MSH6):c.3991C>T (p.Arg1331Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

25 submissions

25 submitters

10 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.3991C>T (p.Arg1331Ter)

Variation ID: 42472 Accession: VCV000042472.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47806641 (GRCh38) [ NCBI UCSC ] 2: 48033780 (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 8, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.3991C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Arg1331Ter	nonsense
NM_001281492.2:c.3601C>T	NP_001268421.1:p.Arg1201Ter	nonsense
NM_001281493.2:c.3085C>T	NP_001268422.1:p.Arg1029Ter	nonsense
NM_001281494.2:c.3085C>T	NP_001268423.1:p.Arg1029Ter	nonsense
NC_000002.12:g.47806641C>T
NC_000002.11:g.48033780C>T
NG_007111.1:g.28495C>T
NG_008397.1:g.104035G>A
LRG_219:g.28495C>T
LRG_219t1:c.3991C>T	LRG_219p1:p.Arg1331Ter

... more HGVS ... less HGVS

Protein change

R1331*, R1029*, R1201*

Other names

p.R1331*:CGA>TGA

Canonical SPDI

NC_000002.12:47806640:C:T

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA015060 dbSNP: rs267608094 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	9161	9479

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 (3)	reviewed by expert panel	Sep 5, 2013	RCV000035325.16
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 27, 2024	RCV000131743.15
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	May 14, 2024	RCV000202305.22
Lynch syndrome 5	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	May 31, 2023	RCV000410467.11
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV000524203.11
Hereditary nonpolyposis colon cancer	Pathogenic (1)	criteria provided, single submitter	Jan 26, 2022	RCV001824584.3
Endometrial carcinoma Lynch syndrome 5 Mismatch repair cancer syndrome 3	Pathogenic (1)	criteria provided, single submitter	Mar 17, 2022	RCV002490471.3
Endometrial carcinoma	Pathogenic (1)	criteria provided, single submitter	Feb 21, 2023	RCV003460548.1
Breast and/or ovarian cancer	Pathogenic (1)	criteria provided, single submitter	Feb 6, 2023	RCV003492340.1
MSH6-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 4, 2024	RCV004528168.2

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: SCV000108181.3 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 (variant causes splicing aberration)
Pathogenic (Jan 26, 2022)	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: SCV000695906.3 First in ClinVar: Dec 26, 2017 Last updated: Feb 12, 2022	Publications: PubMed (8) PubMed: 16418736‚ 21056691‚ 21642682‚ 22081473‚ 20587412‚ 26681312‚ 26552419‚ 26318770 Comment: Variant summary: MSH6 c.3991C>T (p.Arg1331X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: MSH6 c.3991C>T (p.Arg1331X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 245746 control chromosomes (gnomAD). c.3991C>T has been reported in the literature in individuals affected with varying cancer phenotypes including colorectal (Sjursen_2010, Limburg_2011, van Lier_2012, Lavoine_2015), endometrial (Goodfellow_2015), and breast (Susswein_2016), and in individuals with a family history of Lynch syndrome (Plaschke_2006). These data indicate that the variant is very likely to be associated with disease. The variant has, however, also been reported in seemingly healthy individuals, including the father of a compound heterozygote child with Lynch Syndrome, indicating that it may exhibit reduced penetrance (Plaschke_2006). One publication reports experimental evidence indicating that the variant results in exon 9 skipping (Plaschke_2006), and multiple publications report a reduction of IHC staining for MSH6 protein in samples from individuals with this variant. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (May 27, 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: SCV000186784.10 First in ClinVar: Aug 06, 2014 Last updated: Aug 11, 2024	Publications: PubMed (16) PubMed: 18409202‚ 20531397‚ 21056691‚ 21674763‚ 22081473‚ 24362816‚ 24989436‚ 26318770‚ 26681312‚ 27380347‚ 27601186‚ 29345684‚ 30322717‚ 31054147‚ 31501241‚ 32775946 Comment: The p.R1331* pathogenic mutation (also known as c.3991C>T), located in coding exon 9 of the MSH6 gene, results from a C to T substitution at … (more) The p.R1331* pathogenic mutation (also known as c.3991C>T), located in coding exon 9 of the MSH6 gene, results from a C to T substitution at nucleotide position 3991. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in multiple individuals with Lynch syndrome (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; van Lier MG et al. J. Pathol. 2012 Apr;226:764-74; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835), including at least one with breast cancer (Roberts ME et al. Genet. Med. 2018 10;20:1167-1174) and one individual with ovarian cancer (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). This mutation has also been reported in the homozygous state in an individual with constitutional mismatch repair deficiency who was diagnosed with multiple café-au-lait macules and colorectal cancer at age 11 (Lavoine N et al. Med. Genet. 2015 Nov;52:770-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Feb 02, 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: SCV000488239.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 16418736‚ 21056691‚ 20587412
Pathogenic (Feb 06, 2022)	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: SCV000601596.3 First in ClinVar: Sep 28, 2017 Last updated: Dec 31, 2022	Publications: PubMed (17) PubMed: 21642682‚ 18301448‚ 16034045‚ 21056691‚ 16418736‚ 26318770‚ 20587412‚ 26552419‚ 18409202‚ 22081473‚ 27601186‚ 33471991‚ 30322717‚ 26681312‚ 31054147‚ 31447099‚ 27380347 Comment: This nonsense variant causes the premature termination of MSH6 protein synthesis. A published experimental study indicated that this variant results in partial skipping of exon … (more) This nonsense variant causes the premature termination of MSH6 protein synthesis. A published experimental study indicated that this variant results in partial skipping of exon 9 (PMID: 16418736). Additionally, this variant has been reported in individuals with breast (PMID: 26681312 (2016)), ovarian (PMID: 30322717 (2018)), endometrial (PMIDs: 16034045 (2005) and 26552419 (2015)), colorectal (PMIDs: 20587412 (2010), 21056691 (2011), 22081473 (2012), 26318770 (2015), and 27601186 (2016)), and other lynch-related cancers whose tumors showed loss of MSH6 expression in the immunohistochemistry staining (PMIDs: 16034045 (2005), 18301448 (2008), 20587412 (2010), and 22081473 (2012)). In addition, this variant has also been reported in a couple of individuals with constitutional mismatch repair syndrome in the compound heterozygous state with another pathogenic MSH6 variant or in the homozygous state (PMIDs: 16418736 (2006) and 26318770 (2015)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Mar 17, 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: SCV002790837.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Mar 30, 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: SCV004019084.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (1) PubMed: 16418736 Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. Functional studies indicate this variant … (more) This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. Functional studies indicate this variant impacts protein function [PMID:16418736]. (less)
Pathogenic (Feb 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004195832.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Feb 06, 2023)	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: SCV004239322.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Jan 08, 2024)	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: SCV004835190.1 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)	Comment: The c.3991C>T (p.Arg1331) variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated … (more) The c.3991C>T (p.Arg1331) variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome-associated tumors and loss of MSH6 expression through immunohistochemistry staining were identified in the tumors of these individuals (PMID 16034045,18301448, 20587412). This variant has also been reported in two individuals with constitutional mismatch repair syndrome. One the two individuals carry this variant in trans with a likely pathogenic MSH6 variant (p.Arg1076Cys, PMID 16418736) and the other individual was homozygous with this variant (PMID 26318770). This variant is extremely rare in general population databases. Therefore, this c.3991C>T (p.Arg1331*) variant in the MSH6 gene is classified as pathogenic. (less) Number of individuals with the variant: 2
Pathogenic (Oct 27, 2021)	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: SCV000058973.7 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (8) PubMed: 16418736‚ 22810696‚ 16034045‚ 18301448‚ 21642682‚ 20587412‚ 26318770‚ 26681312 Comment: The p.Arg1331X variant in MSH6 has been reported in the heterozygous state in 6 individuals with MSH6-associated cancers, some of whose tumors demonstrated loss of … (more) The p.Arg1331X variant in MSH6 has been reported in the heterozygous state in 6 individuals with MSH6-associated cancers, some of whose tumors demonstrated loss of MSH6 expression on immunohistochemistry (IHC) analysis (Stormorken 2005 PMID:16034045, Sjursen 2010 PMID:20587412, Bonadona 2011 PMID:21642682, Susswein 2015 PMID:26681312, LMM data). This variant has also been reported in 2 individuals with clinical features of constitutional mismatch repair syndrome in the compound heterozygous state with another MSH6 variant (Plaschke 2006 PMID:16418736) or in the homozygous state (Lavoine 2015 PMID:26318770). In addition, the p.Arg1331X variant has been identified in 0.001% (1/67908) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1331. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. This has been corroborated by studies have demonstrated that the variant results in skipping of exon 9, giving rise to a truncated mRNA leading to drastically reduced MSH6 protein levels, suggesting that this truncated protein is unstable (Plaschke 2006 PMID:16418736). Moreover, the p.Arg1331X variant has been classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108181.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PVS1_Strong, PM3, PS3_Moderate. (less)
Pathogenic (Feb 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429321.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Number of individuals with the variant: 1
Pathogenic (Oct 14, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary non-polyposis colorectal cancer, type 5 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434868.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: The c.3991C>T (p.Arg1331) variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated … (more) The c.3991C>T (p.Arg1331) variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome-associated tumors and loss of MSH6 expression through immunohistochemistry staining were identified in the tumors of these individuals (PMID 16034045,18301448, 20587412). This variant has also been reported in two individuals with constitutional mismatch repair syndrome. One the two individuals carry this variant in trans with a likely pathogenic MSH6 variant (p.Arg1076Cys, PMID 16418736) and the other individual was homozygous with this variant (PMID 26318770). This variant is extremely rare in general population databases. Therefore, this c.3991C>T (p.Arg1331*) variant in the MSH6 gene is classified as pathogenic. (less)
Pathogenic (Oct 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580515.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PVS1_MOD, PS4_MOD, PM3, PP1	Number of individuals with the variant: 1 Sex: male
Pathogenic (Sep 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: germline	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002757861.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022
Pathogenic (Jun 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026435.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Observation 1: Observation 2:
Pathogenic (May 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004042787.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: ACMG criteria used to clasify this variant:PVS1, PS4_MOD, PM1, PS3_SUP, PM2_SUP
Pathogenic (Feb 21, 2023)	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: SCV001340973.3 First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 16034045‚ 16418736‚ 20587412‚ 21056691‚ 21674763‚ 22081473‚ 26318770‚ 26552419‚ 27601186‚ 29345684 Comment: This variant changes 1 nucleotide in exon 9 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 9 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal and/or endometrial cancer, Lynch syndrome, and Constitutional mismatch repair-deficiency syndrome (PMID: 16034045, 16418736, 20587412, 21056691, 21674763, 22081473, 26318770, 26552419, 27601186, 29345684). This variant has been identified in 1/245746 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 (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: SCV000283835.10 First in ClinVar: May 29, 2016 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 28492532‚ 16034045‚ 18301448‚ 20587412‚ 21056691‚ 21642682‚ 27601186‚ 16418736‚ 19851887‚ 21155762 Comment: This sequence change creates a premature translational stop signal (p.Arg1331) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg1331) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs267608094, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16034045, 18301448, 20587412, 21056691, 21642682, 27601186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 42472). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MSH6 function (PMID: 16418736). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 14, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000211329.18 First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024	Comment: Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost, and also demonstrated to result in … (more) Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost, and also demonstrated to result in partial skipping of exon 9 (PMID: 16418736); Observed in the homozygous or compound heterozygous state in individuals with a personal history consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 26318770); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24989436, 25525159, 18409202, 18709565, 26681312, 26552419, 26318770, 12019211, 22081473, 16034045, 21056691, 21674763, 21376568, 18301448, 21642682, 16418736, 27601186, 24362816, 19851887, 30322717, 31447099, 32019277, 21120944, 17531815, 33087929, 34445333, 32427313, 30787465, 28888541, 29922827, 36744932, 29345684, 20587412, 27380347, 31054147) (less)
Likely pathogenic (-)	no assertion criteria provided Method: research	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257292.1 First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015	Number of individuals with the variant: 1
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952768.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001969250.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744264.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (Jun 04, 2024)	no assertion criteria provided Method: clinical testing	MSH6-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004106058.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The MSH6 c.3991C>T variant is predicted to result in premature protein termination (p.Arg1331). This variant has been repeatedly reported in the heterozygous state in individuals … (more) The MSH6 c.3991C>T variant is predicted to result in premature protein termination (p.Arg1331). This variant has been repeatedly reported in the heterozygous state in individuals with variable cancer phenotypes, including patients with colorectal, endometrial, and breast cancer (see for example Sjursen et al. 2010. PubMed ID: 20587412; Goodfellow et al. 2015. PubMed ID: 26552419; Susswein et al. 2016. PubMed ID: 26681312). This variant has also been reported in the homozygous and compound heterozygous states in patients with constitutional mismatch repair syndrome (see for example Plaschke et al. 2006. PubMed ID: 16418736; Lavoine et al. 2015. PubMed ID: 26318770). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/42472/). Nonsense variants in MSH6 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. (less)
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Comment:

Variant summary: MSH6 c.3991C>T (p.Arg1331X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 245746 control chromosomes (gnomAD). c.3991C>T has been reported in the literature in individuals affected with varying cancer phenotypes including colorectal (Sjursen_2010, Limburg_2011, van Lier_2012, Lavoine_2015), endometrial (Goodfellow_2015), and breast (Susswein_2016), and in individuals with a family history of Lynch syndrome (Plaschke_2006). These data indicate that the variant is very likely to be associated with disease. The variant has, however, also been reported in seemingly healthy individuals, including the father of a compound heterozygote child with Lynch Syndrome, indicating that it may exhibit reduced penetrance (Plaschke_2006). One publication reports experimental evidence indicating that the variant results in exon 9 skipping (Plaschke_2006), and multiple publications report a reduction of IHC staining for MSH6 protein in samples from individuals with this variant. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The p.R1331* pathogenic mutation (also known as c.3991C>T), located in coding exon 9 of the MSH6 gene, results from a C to T substitution at nucleotide position 3991. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in multiple individuals with Lynch syndrome (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; van Lier MG et al. J. Pathol. 2012 Apr;226:764-74; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835), including at least one with breast cancer (Roberts ME et al. Genet. Med. 2018 10;20:1167-1174) and one individual with ovarian cancer (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). This mutation has also been reported in the homozygous state in an individual with constitutional mismatch repair deficiency who was diagnosed with multiple café-au-lait macules and colorectal cancer at age 11 (Lavoine N et al. Med. Genet. 2015 Nov;52:770-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

This nonsense variant causes the premature termination of MSH6 protein synthesis. A published experimental study indicated that this variant results in partial skipping of exon 9 (PMID: 16418736). Additionally, this variant has been reported in individuals with breast (PMID: 26681312 (2016)), ovarian (PMID: 30322717 (2018)), endometrial (PMIDs: 16034045 (2005) and 26552419 (2015)), colorectal (PMIDs: 20587412 (2010), 21056691 (2011), 22081473 (2012), 26318770 (2015), and 27601186 (2016)), and other lynch-related cancers whose tumors showed loss of MSH6 expression in the immunohistochemistry staining (PMIDs: 16034045 (2005), 18301448 (2008), 20587412 (2010), and 22081473 (2012)). In addition, this variant has also been reported in a couple of individuals with constitutional mismatch repair syndrome in the compound heterozygous state with another pathogenic MSH6 variant or in the homozygous state (PMIDs: 16418736 (2006) and 26318770 (2015)). Based on the available information, this variant is classified as pathogenic.

Comment:

The c.3991C>T (p.Arg1331*) variant in the MSH6 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with Lynch Syndrome-associated tumors and loss of MSH6 expression through immunohistochemistry staining were identified in the tumors of these individuals (PMID 16034045,18301448, 20587412). This variant has also been reported in two individuals with constitutional mismatch repair syndrome. One the two individuals carry this variant in trans with a likely pathogenic MSH6 variant (p.Arg1076Cys, PMID 16418736) and the other individual was homozygous with this variant (PMID 26318770). This variant is extremely rare in general population databases. Therefore, this c.3991C>T (p.Arg1331*) variant in the MSH6 gene is classified as pathogenic.

Comment:

The p.Arg1331X variant in MSH6 has been reported in the heterozygous state in 6 individuals with MSH6-associated cancers, some of whose tumors demonstrated loss of MSH6 expression on immunohistochemistry (IHC) analysis (Stormorken 2005 PMID:16034045, Sjursen 2010 PMID:20587412, Bonadona 2011 PMID:21642682, Susswein 2015 PMID:26681312, LMM data). This variant has also been reported in 2 individuals with clinical features of constitutional mismatch repair syndrome in the compound heterozygous state with another MSH6 variant (Plaschke 2006 PMID:16418736) or in the homozygous state (Lavoine 2015 PMID:26318770). In addition, the p.Arg1331X variant has been identified in 0.001% (1/67908) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1331. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. This has been corroborated by studies have demonstrated that the variant results in skipping of exon 9, giving rise to a truncated mRNA leading to drastically reduced MSH6 protein levels, suggesting that this truncated protein is unstable (Plaschke 2006 PMID:16418736). Moreover, the p.Arg1331X variant has been classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108181.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PVS1_Strong, PM3, PS3_Moderate.

Comment:

This variant changes 1 nucleotide in exon 9 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal and/or endometrial cancer, Lynch syndrome, and Constitutional mismatch repair-deficiency syndrome (PMID: 16034045, 16418736, 20587412, 21056691, 21674763, 22081473, 26318770, 26552419, 27601186, 29345684). This variant has been identified in 1/245746 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:

This sequence change creates a premature translational stop signal (p.Arg1331*) in the MSH6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the MSH6 protein. This variant is present in population databases (rs267608094, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16034045, 18301448, 20587412, 21056691, 21642682, 27601186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 42472). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MSH6 function (PMID: 16418736). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). This variant disrupts a region of the MSH6 protein in which other variant(s) (p.Leu1330Valfs*12) have been determined to be pathogenic (PMID: 19851887, 21155762). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost, and also demonstrated to result in partial skipping of exon 9 (PMID: 16418736); Observed in the homozygous or compound heterozygous state in individuals with a personal history consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 26318770); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24989436, 25525159, 18409202, 18709565, 26681312, 26552419, 26318770, 12019211, 22081473, 16034045, 21056691, 21674763, 21376568, 18301448, 21642682, 16418736, 27601186, 24362816, 19851887, 30322717, 31447099, 32019277, 21120944, 17531815, 33087929, 34445333, 32427313, 30787465, 28888541, 29922827, 36744932, 29345684, 20587412, 27380347, 31054147)

Comment:

The MSH6 c.3991C>T variant is predicted to result in premature protein termination (p.Arg1331*). This variant has been repeatedly reported in the heterozygous state in individuals with variable cancer phenotypes, including patients with colorectal, endometrial, and breast cancer (see for example Sjursen et al. 2010. PubMed ID: 20587412; Goodfellow et al. 2015. PubMed ID: 26552419; Susswein et al. 2016. PubMed ID: 26681312). This variant has also been reported in the homozygous and compound heterozygous states in patients with constitutional mismatch repair syndrome (see for example Plaschke et al. 2006. PubMed ID: 16418736; Lavoine et al. 2015. PubMed ID: 26318770). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/42472/). Nonsense variants in MSH6 are expected to be pathogenic. Taken together, this variant is interpreted 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
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Paediatric systemic lupus erythematosus as a manifestation of constitutional mismatch repair deficiency.	Toledano H	Journal of medical genetics	2020	PMID: 31501241
Understanding inherited risk in unselected newly diagnosed patients with endometrial cancer.	Cadoo KA	JCO precision oncology	2019	PMID: 32775946
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
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
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.	Roberts ME	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29345684
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.	Lagerstedt-Robinson K	Oncology reports	2016	PMID: 27601186
Tumor Screening and DNA Testing in the Diagnosis of Lynch Syndrome.	Usha L	JAMA	2016	PMID: 27380347
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
Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.	Goodfellow PJ	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 26552419
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.	Lavoine N	Journal of medical genetics	2015	PMID: 26318770
A review of mismatch repair gene transcripts: issues for interpretation of mRNA splicing assays.	Thompson BA	Clinical genetics	2015	PMID: 24989436
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
Comprehensive molecular characterization of human colon and rectal cancer.	Cancer Genome Atlas Network	Nature	2012	PMID: 22810696
Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome.	van Lier MG	The Journal of pathology	2012	PMID: 22081473
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
Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome.	Raskin L	Clinical genetics	2011	PMID: 21155762
Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer.	Limburg PJ	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association	2011	PMID: 21056691
Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.	Sjursen W	Journal of medical genetics	2010	PMID: 20587412
The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations.	Durno CA	The American journal of gastroenterology	2010	PMID: 20531397
An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.	Goldberg Y	Familial cancer	2010	PMID: 19851887
Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus.	Rahner N	American journal of medical genetics. Part A	2008	PMID: 18409202
No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients.	Steinke V	European journal of human genetics : EJHG	2008	PMID: 18301448
Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor.	Plaschke J	European journal of human genetics : EJHG	2006	PMID: 16418736
Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer.	Stormorken AT	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2005	PMID: 16034045
http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.3991C%3ET	-	-	-	-
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Text-mined citations for rs267608094 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000179.3(MSH6):c.3991C>T (p.Arg1331Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267608094 ...