Coding sequence variation resulting in a stop codon
NM_000535.7(PMS2):c.943C>T (p.Arg315Ter)
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Lynch Syndrome
Classification is based on the expert panel submission
Sep 2013 by
International Society for Gastrointestinal Hereditary Tumou…
Help
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000535.7(PMS2):c.943C>T (p.Arg315Ter)
Variation ID: 91382 Accession: VCV000091382.86
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5992018 (GRCh38) [ NCBI UCSC ] 7: 6031649 (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 Dec 6, 2014 Jul 27, 2026 Sep 5, 2013 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000535.7:c.943C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Arg315Ter nonsense NM_001322003.2:c.538C>T NP_001308932.1:p.Arg180Ter nonsense NM_001322004.2:c.538C>T NP_001308933.1:p.Arg180Ter nonsense NM_001322005.2:c.538C>T NP_001308934.1:p.Arg180Ter nonsense NM_001322006.2:c.943C>T NP_001308935.1:p.Arg315Ter nonsense NM_001322007.2:c.625C>T NP_001308936.1:p.Arg209Ter nonsense NM_001322008.2:c.625C>T NP_001308937.1:p.Arg209Ter nonsense NM_001322009.2:c.538C>T NP_001308938.1:p.Arg180Ter nonsense NM_001322010.2:c.538C>T NP_001308939.1:p.Arg180Ter nonsense NM_001322011.2:c.10C>T NP_001308940.1:p.Arg4Ter nonsense NM_001322012.2:c.10C>T NP_001308941.1:p.Arg4Ter nonsense NM_001322013.2:c.370C>T NP_001308942.1:p.Arg124Ter nonsense NM_001322014.2:c.943C>T NP_001308943.1:p.Arg315Ter nonsense NM_001322015.2:c.634C>T NP_001308944.1:p.Arg212Ter nonsense NR_136154.1:n.1030C>T non-coding transcript variant NC_000007.14:g.5992018G>A NC_000007.13:g.6031649G>A NG_008466.1:g.22089C>T LRG_161:g.22089C>T LRG_161t1:c.943C>T - Protein change
- R315*, R209*, R180*, R212*, R124*, R4*
- Other names
-
p.R315*:CGA>TGA
- Canonical SPDI
- NC_000007.14:5992017:G:A
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Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6154 | 6264 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000076901.11 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 10, 2025 | RCV000115711.19 | |
|
Colorectal cancer, non-polyposis
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148734.6 |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000212858.48 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 19, 2026 | RCV000524484.13 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 2, 2025 | RCV000576503.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763587.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001354630.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2021 | RCV003162501.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 21, 2024 | RCV005042191.1 |
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. |
Expand all rows
Collapse all rows
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. |
|
|---|---|---|---|---|---|
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Pathogenic
(Sep 05, 2013)
C
Contributing to aggregate classification
|
reviewed by expert panel
|
Lynch Syndrome |
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108398.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 31, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Mismatch repair cancer syndrome 1
Lynch syndrome 4 |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894426.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Nov 07, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888422.2
First in ClinVar: Dec 19, 2017 Last updated: Jan 01, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 25, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Sema4, Sema4
Accession: SCV002530410.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PMS2 c.943C>T (p. R315X) variant has been reported in heterozygosity in multiple individuals with colorectal cancer. Immunohistochemical tumor testing showed reduced mismatch repair activity … (more)
The PMS2 c.943C>T (p. R315X) variant has been reported in heterozygosity in multiple individuals with colorectal cancer. Immunohistochemical tumor testing showed reduced mismatch repair activity in vitro and absent PMS2 expression (PMID: 20205264, 22918162, 23709753, 25477341, 27589204, 25856668). This variant has also been observed in heterozygosity in individuals with breast cancer (26681312, 28724667, 31784482) and ovarian cancer (31056861). This nonsense variant creates a premature stop codon at residue 315 of the PMS2 protein. Loss of function variants in PMS2 are known to be pathogenic (PMID: 24362816) This variant was observed in 1/10366 chromosomes in the Ashkenazi Jewish population, with no homozygotes, according to the Genome Aggregation Database (PMID: 27535533). This variant has been classified as pathogenic by a ClinGen-approved expert panel. Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Aug 04, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000149620.16
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
show
Nonsense 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 individuals with MSI-H and/or PMS2 absent colorectal cancer (Vaughn 2010, Borras 2013, Shia 2013, Hinrichsen 2015, Goodenberger 2016, Sugano 2016, Wang 2020); Published functional studies demonstrate a damaging effect: loss of PMS2 expression and reduced MMR activity (Hinrichsen 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 32885271, 32719484, 25477341, 23709753, 20205264, 22918162, 25856668, 27589204, 31992580, 31784482, 31297337, 30521064, 26681312, 28724667, 25111426, 26046366, 25430799, 25525159, 25637381) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
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Pathogenic
(Apr 05, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4 |
Myriad Genetics, Inc.
Accession: SCV004019893.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
show
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
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Pathogenic
(Oct 03, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4 |
Baylor Genetics
Accession: SCV004205420.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jul 01, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001502552.36
First in ClinVar: Mar 14, 2021 Last updated: Jul 27, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 2
|
|
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Pathogenic
(Jan 31, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338126.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
show
Variant summary: PMS2 c.943C>T (p.Arg315X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251270 control chromosomes. c.943C>T has been reported in the literature in individuals affected with Lynch Syndrome or breast cancer (Susswein_2016, Latham_2019). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 27, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847561.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
show
The p.Arg315X variant in PMS2 has been reported in at least 9 individuals with PMS2-associated cancers and segregated with disease in at least 2 affected individuals from one family (Vaughn 2010 PMID: 20205264, Borras 2013 PMID: 23709753, Sugano 2016 PMID: 27589204, Susswein 2016 PMID: 26681312, Sun 2017 PMID: 28724667, Jiang 2019 PMID: 30521064, Lerner-Ellis 2021 PMID: 32885271, Wang 2020 PMID: 31992580). It has also been identified in 0.01% (1/10366) of Ashkenazi Jewish chromosomes, 0.005% (1/19950) of East Asian chromosomes and 0.004% (1/24956) of Afircan/African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 315, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. Additionally, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 91382). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Nov 15, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4 |
New York Genome Center
Study: PrenatalSEQ
Accession: SCV005044161.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
show
The c.943C>T variant in PMS2 has previously been reported in individuals or families with lynch syndrome and colon cancer [PMID: 20205264, 22918162, 23709753, 25856668, 27589204, 31297337, 31992580]. This variant was also identified in an asymptomatic carrier from a Lynch syndrome family [PMID: 23709753] and it has been deposited in ClinVar [ClinVar ID: 91382] as Pathogenic. The c.943C>T variant is observed in 14 alleles (~0.0017% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.943C>T variant in PMS2 is located in exon 9 of this 15-exon gene, predicted to incorporate a premature termination codon p.(Arg315Ter), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.943C>T variant have been reported in the literature [PMID: 31992580] and ClinVar [ClinVar ID: 91299] in individuals with Lynch syndrome. In vitro functional studies demonstrated reduced mismatch repair activity and lack of full length PMS2 protein expression in human embryonic kidney cells (HEK293T) carrying c.943C>T variant [PMID: 25477341]. Based on available evidence this inherited c.943C>T p.(Arg315Ter) variant identified in PMS2 is classified here as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: inherited
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: inherited
Affected status: unknown
Clinical Features:
Fetal pleural effusion (present)
Test name: whole genome sequencing
Zygosity: 1 Single Heterozygote
Age: 20-29 weeks gestation
Secondary finding: yes
Platform name: NovaSeq 6000
|
|
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Pathogenic
(Sep 24, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome
(Autosomal dominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV004839876.2
First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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:
show
This variant changes 1 nucleotide in exon 9 of the PMS2 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 Lynch syndrome (PMID: 30376427) and colorectal cancer with tumors showing loss of PMS2 expression and/or microsatellite instability (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). This variant has also been reported in an individual affected with breast cancer (PMID: 28724667). This variant has been identified in 5/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 9
Zygosity: 9 Single Heterozygotes
|
|
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Pathogenic
(Feb 21, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4
Mismatch repair cancer syndrome 4
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Fulgent Genetics, Fulgent Genetics
Accession: SCV005674335.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Feb 08, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000212770.8
First in ClinVar: Mar 24, 2015 Last updated: Apr 28, 2025 |
Comment:
show
The p.R315* pathogenic mutation (also known as c.943C>T), located in coding exon 9 of the PMS2 gene, results from a C to T substitution at nucleotide position 943. 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 hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated high microsatellite instability and/or absent PMS2 by immunohistochemistry (IHC) (Vaughn CP et al. Hum Mutat, 2010 May;31:588-93; Shia J et al. Mod. Pathol., 2013 Jan;26:131-8; Borràs E et al. J Med Genet, 2013 Aug;50:552-63; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686; Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Guo X et al. Mol Genet Genomic Med, 2019 06;7:e721; Maynard H et al. Cancer, 2020 01;126:1995-2002; Wang Q et al. J Med Genet, 2020 07;57:487-499; Choi YY et al. Sci Rep, 2021 07;11:14807). Pathogenicity of this mutation has been supported by a functional assay showing reduced mismatch repair activity in vitro and lack of full length PMS2 protein expression (Hinrichsen I et al. Carcinogenesis. 2015 Feb;36:202-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Mar 10, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000691128.5
First in ClinVar: Feb 19, 2018 Last updated: May 03, 2025 |
Comment:
show
This variant changes 1 nucleotide in exon 9 of the PMS2 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 Lynch syndrome associated cancers with tumors showing loss of PMS2 expression and/or microsatellite instability (PMID: 20205264, 22918162, 23709753, 25856668, 27589204, 30376427, 30521064, 31056861, 31992580, 34285288). This variant has been identified in 5/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
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Pathogenic
(Nov 16, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV002018888.4
First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
pathogenic
(Jul 02, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV006324910.1
First in ClinVar: Sep 22, 2025 Last updated: Sep 22, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Sex: male
|
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Pathogenic
(Jan 19, 2026)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary nonpolyposis colorectal neoplasms |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000261298.12
First in ClinVar: Mar 24, 2015 Last updated: Feb 23, 2026 |
Comment:
show
This sequence change creates a premature translational stop signal (p.Arg315*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is present in population databases (rs200640585, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and colon cancer (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,627,235 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 91382). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Malignant tumor of breast |
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549291.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
show
The PMS2 p.Arg315* variant was identified in 5 of 2648 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Borras 2013, Goldberg 2015, Goodenberger 2016, Sugano 2016, Vaughn 2010). The variant was also identified in dbSNP (ID: rs200640585) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and four other submitters). The variant was identified in control databases in 6 of 277038 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.00004), European in 3 of 126694 chromosomes (freq: 0.00002), Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001), and East Asian in 1 of 18866 chromosomes (freq: 0.00005); it was not observed in the Other, Latino, Finnish, or South Asian populations. The p.Arg315* variant leads to a premature stop codon at position 315, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
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Pathogenic
(Jul 01, 2021)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Gastric cancer |
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758146.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
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Pathogenic
(Oct 02, 2015)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Lynch syndrome 4 |
Counsyl
Accession: SCV000677745.3
First in ClinVar: Jan 07, 2018 Last updated: Jun 29, 2025 |
Comment:
show
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
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Pathogenic
(Jun 01, 2014)
N
Not contributing to aggregate classification
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no assertion criteria provided
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Colorectal cancer, non-polyposis
(Autosomal dominant inheritance)
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190469.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
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Comment:
Comment:
Nonsense 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 individuals with MSI-H and/or PMS2 absent colorectal cancer (Vaughn 2010, Borras 2013, Shia 2013, Hinrichsen 2015, Goodenberger 2016, Sugano 2016, Wang 2020); Published functional studies demonstrate a damaging effect: loss of PMS2 expression and reduced MMR activity (Hinrichsen 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 32885271, 32719484, 25477341, 23709753, 20205264, 22918162, 25856668, 27589204, 31992580, 31784482, 31297337, 30521064, 26681312, 28724667, 25111426, 26046366, 25430799, 25525159, 25637381)
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
PMS2: PVS1, PM2, PS4:Moderate
Comment:
Variant summary: PMS2 c.943C>T (p.Arg315X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251270 control chromosomes. c.943C>T has been reported in the literature in individuals affected with Lynch Syndrome or breast cancer (Susswein_2016, Latham_2019). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The p.Arg315X variant in PMS2 has been reported in at least 9 individuals with PMS2-associated cancers and segregated with disease in at least 2 affected individuals from one family (Vaughn 2010 PMID: 20205264, Borras 2013 PMID: 23709753, Sugano 2016 PMID: 27589204, Susswein 2016 PMID: 26681312, Sun 2017 PMID: 28724667, Jiang 2019 PMID: 30521064, Lerner-Ellis 2021 PMID: 32885271, Wang 2020 PMID: 31992580). It has also been identified in 0.01% (1/10366) of Ashkenazi Jewish chromosomes, 0.005% (1/19950) of East Asian chromosomes and 0.004% (1/24956) of Afircan/African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 315, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. Additionally, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 91382). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate.
Comment:
The c.943C>T variant in PMS2 has previously been reported in individuals or families with lynch syndrome and colon cancer [PMID: 20205264, 22918162, 23709753, 25856668, 27589204, 31297337, 31992580]. This variant was also identified in an asymptomatic carrier from a Lynch syndrome family [PMID: 23709753] and it has been deposited in ClinVar [ClinVar ID: 91382] as Pathogenic. The c.943C>T variant is observed in 14 alleles (~0.0017% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.943C>T variant in PMS2 is located in exon 9 of this 15-exon gene, predicted to incorporate a premature termination codon p.(Arg315Ter), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.943C>T variant have been reported in the literature [PMID: 31992580] and ClinVar [ClinVar ID: 91299] in individuals with Lynch syndrome. In vitro functional studies demonstrated reduced mismatch repair activity and lack of full length PMS2 protein expression in human embryonic kidney cells (HEK293T) carrying c.943C>T variant [PMID: 25477341]. Based on available evidence this inherited c.943C>T p.(Arg315Ter) variant identified in PMS2 is classified here as Pathogenic.
Comment:
This variant changes 1 nucleotide in exon 9 of the PMS2 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 Lynch syndrome (PMID: 30376427) and colorectal cancer with tumors showing loss of PMS2 expression and/or microsatellite instability (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). This variant has also been reported in an individual affected with breast cancer (PMID: 28724667). This variant has been identified in 5/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.R315* pathogenic mutation (also known as c.943C>T), located in coding exon 9 of the PMS2 gene, results from a C to T substitution at nucleotide position 943. 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 hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated high microsatellite instability and/or absent PMS2 by immunohistochemistry (IHC) (Vaughn CP et al. Hum Mutat, 2010 May;31:588-93; Shia J et al. Mod. Pathol., 2013 Jan;26:131-8; Borràs E et al. J Med Genet, 2013 Aug;50:552-63; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686; Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Guo X et al. Mol Genet Genomic Med, 2019 06;7:e721; Maynard H et al. Cancer, 2020 01;126:1995-2002; Wang Q et al. J Med Genet, 2020 07;57:487-499; Choi YY et al. Sci Rep, 2021 07;11:14807). Pathogenicity of this mutation has been supported by a functional assay showing reduced mismatch repair activity in vitro and lack of full length PMS2 protein expression (Hinrichsen I et al. Carcinogenesis. 2015 Feb;36:202-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant changes 1 nucleotide in exon 9 of the PMS2 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 Lynch syndrome associated cancers with tumors showing loss of PMS2 expression and/or microsatellite instability (PMID: 20205264, 22918162, 23709753, 25856668, 27589204, 30376427, 30521064, 31056861, 31992580, 34285288). This variant has been identified in 5/282632 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Criteria applied: PVS1,PP4_SUP,PM2_SUP
Comment:
This sequence change creates a premature translational stop signal (p.Arg315*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is present in population databases (rs200640585, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and colon cancer (PMID: 20205264, 22918162, 23709753, 25856668, 27589204). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,627,235 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 91382). For these reasons, this variant has been classified as Pathogenic.
Comment:
The PMS2 p.Arg315* variant was identified in 5 of 2648 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Borras 2013, Goldberg 2015, Goodenberger 2016, Sugano 2016, Vaughn 2010). The variant was also identified in dbSNP (ID: rs200640585) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and four other submitters). The variant was identified in control databases in 6 of 277038 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.00004), European in 3 of 126694 chromosomes (freq: 0.00002), Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001), and East Asian in 1 of 18866 chromosomes (freq: 0.00005); it was not observed in the Other, Latino, Finnish, or South Asian populations. The p.Arg315* variant leads to a premature stop codon at position 315, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
| Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers. | Choi YY | Scientific reports | 2021 | PMID: 34285288 |
| Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
| Germline alterations in patients with biliary tract cancers: A spectrum of significant and previously underappreciated findings. | Maynard H | Cancer | 2020 | PMID: 32012241 |
| Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. | Wang Q | Journal of medical genetics | 2020 | PMID: 31992580 |
| Identification of Germline Mismatch Repair Gene Mutations in Lung Cancer Patients With Paired Tumor-Normal Next Generation Sequencing: A Retrospective Study. | Sun S | Frontiers in oncology | 2019 | PMID: 31297337 |
| PMS2 germline mutation c.943C>T (p.Arg315*)-induced Lynch syndrome-associated ovarian cancer. | Guo X | Molecular genetics & genomic medicine | 2019 | PMID: 31056861 |
| Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features. | Jiang W | International journal of cancer | 2019 | PMID: 30521064 |
| Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. | Latham A | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30376427 |
| 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 |
| Germline PMS2 mutation screened by mismatch repair protein immunohistochemistry of colorectal cancer in Japan. | Sugano K | Cancer science | 2016 | PMID: 27589204 |
| 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 |
| PMS2 monoallelic mutation carriers: the known unknown. | Goodenberger ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 25856668 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Functional testing strategy for coding genetic variants of unclear significance in MLH1 in Lynch syndrome diagnosis. | Hinrichsen I | Carcinogenesis | 2015 | PMID: 25477341 |
| Genetic features of Lynch syndrome in the Israeli population. | Goldberg Y | Clinical genetics | 2015 | PMID: 25430799 |
| 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 |
| Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. | Borràs E | Journal of medical genetics | 2013 | PMID: 23709753 |
| Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency. | Shia J | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2013 | PMID: 22918162 |
| Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines. | Herkert JC | European journal of cancer (Oxford, England : 1990) | 2011 | PMID: 21376568 |
| Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. | Vaughn CP | Human mutation | 2010 | PMID: 20205264 |
| [Effects of exercise on nasal patency]. | Ohki M | Nihon Jibiinkoka Gakkai kaiho | 1988 | PMID: 3199258 |
| http://www.insight-database.org/classifications/index.html?gene=PMS2&variant=c.943C%3ET | - | - | - | - |
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Record last updated Jul 27, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.