ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.1882C>T (p.Arg628Ter)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000535.7(PMS2):c.1882C>T (p.Arg628Ter)
Variation ID: 9242 Accession: VCV000009242.32
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p22.1 7: 5986883 (GRCh38) [ NCBI UCSC ] 7: 6026514 (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 May 1, 2024 Sep 5, 2013 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000535.7:c.1882C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Arg628Ter nonsense NM_001322003.2:c.1477C>T NP_001308932.1:p.Arg493Ter nonsense NM_001322004.2:c.1477C>T NP_001308933.1:p.Arg493Ter nonsense NM_001322005.2:c.1477C>T NP_001308934.1:p.Arg493Ter nonsense NM_001322006.2:c.1726C>T NP_001308935.1:p.Arg576Ter nonsense NM_001322007.2:c.1564C>T NP_001308936.1:p.Arg522Ter nonsense NM_001322008.2:c.1564C>T NP_001308937.1:p.Arg522Ter nonsense NM_001322009.2:c.1477C>T NP_001308938.1:p.Arg493Ter nonsense NM_001322010.2:c.1321C>T NP_001308939.1:p.Arg441Ter nonsense NM_001322011.2:c.949C>T NP_001308940.1:p.Arg317Ter nonsense NM_001322012.2:c.949C>T NP_001308941.1:p.Arg317Ter nonsense NM_001322013.2:c.1309C>T NP_001308942.1:p.Arg437Ter nonsense NM_001322014.2:c.1882C>T NP_001308943.1:p.Arg628Ter nonsense NM_001322015.2:c.1573C>T NP_001308944.1:p.Arg525Ter nonsense NR_136154.1:n.1969C>T non-coding transcript variant NC_000007.14:g.5986883G>A NC_000007.13:g.6026514G>A NG_008466.1:g.27224C>T LRG_161:g.27224C>T LRG_161t1:c.1882C>T - Protein change
- R628*, R317*, R493*, R522*, R576*, R437*, R441*, R525*
- Other names
- -
- Canonical SPDI
- NC_000007.14:5986882:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
- 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 |
5242 | 5344 |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 12, 2023 | RCV000009823.10 | |
Pathogenic (1) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000076834.5 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 7, 2023 | RCV000220439.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 27, 2023 | RCV000218575.12 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 24, 2019 | RCV001193819.1 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 21, 2024 | RCV000524451.10 |
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
Method: research
|
Lynch Syndrome
Affected status: unknown
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108321.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Comment:
Coding sequence variation resulting in a stop codon
|
|
Pathogenic
(Jun 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362953.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PMS2 c.1882C>T (p.Arg628X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PMS2 c.1882C>T (p.Arg628X) 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. RT-PCR analysis on RNA derived from cultured lymphocytes of patients carrying the variant demonstrated nonsense-mediated RNA decay (van der Klift_2010, 2016). The variant allele was found at a frequency of 1.6e-05 in 251434 control chromosomes (gnomAD). c.1882C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Hendriks_2006, Sugano_2016, van der Klift_2010, 2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jun 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000279234.11
First in ClinVar: May 29, 2016 Last updated: Jun 17, 2023 |
Comment:
Observed in individuals with PMS2-related cancers, including those with tumor studies consistent with pathogenic variants in this gene (Hendriks et al., 2006; van Puijenbroek et … (more)
Observed in individuals with PMS2-related cancers, including those with tumor studies consistent with pathogenic variants in this gene (Hendriks et al., 2006; van Puijenbroek et al., 2008; ten Broeke et al., 2015; Suerink et al., 2016; Sugano et al., 2016); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25980754, 20186688, 26110232, 30217226, 28888541, 29758216, 34697415, 25512458, 16472587, 18415027, 25691505, 27589204, 27435373, 28600700, 19283792, 25525159, 30787465, 29625052) (less)
|
|
Pathogenic
(Mar 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019439.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Oct 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000905473.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 11 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 multiple individuals affected with colorectal or endometrial cancer that exhibited microsatellite instability and loss of PMS2 proteins by immunohistochemistry analyses (PMID: 16472587, 18415027, 27589204, 34253388, 36931573). This variant has also been reported in individuals affected with breast cancer (PMID: 16472587, 29345684). This variant has been identified in 4/251434 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)
|
|
Pathogenic
(Mar 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745188.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
Pathogenic
(Aug 06, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002530238.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PMS2 c.1882C>T (p.R628X) variant has been reported in heterozygosity in at least 9 families with hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 16472587, 27589204, 25512458). … (more)
The PMS2 c.1882C>T (p.R628X) variant has been reported in heterozygosity in at least 9 families with hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 16472587, 27589204, 25512458). Functional studies have shown that this variant causes nonsense mediated decay in patient cells (PMID: 27589204) and is expected to result in an absence of the protein product. This variant was observed in 2/33582 chromosomes in the Latino 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)
|
|
|
Pathogenic
(Sep 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004187756.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
Pathogenic
(Oct 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004205394.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jun 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004218966.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This variant causes the premature termination of PMS2 protein synthesis. In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: … (more)
This variant causes the premature termination of PMS2 protein synthesis. In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 27589204 (2016), 27435373 (2016), 16472587 (2006)), breast cancer (PMID: 29345684 (2018)), ovarian/endometrial cancer (PMIDs: 29625052 (2018), 28888541 (2017)), and CMMRD (PMID: 27435373 (2016)). RNA analysis indicated the variant mRNA transcript is subjected to nonsense-mediated decay (PMID: 20186688 (2010)). The frequency of this variant in the general population, 0.000016 (4/251434 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000551972.10
First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg628*) in the PMS2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg628*) 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 (rs63750451, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 16472587, 19283792, 25512458, 26110232, 27435373, 27589204). ClinVar contains an entry for this variant (Variation ID: 9242). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000277667.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.R628* pathogenic mutation (also known as c.1882C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at … (more)
The p.R628* pathogenic mutation (also known as c.1882C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1882. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been reported in several unrelated hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome patients and families; several with tumors demonstrating loss of PMS2 by immunohistochemistry (IHC) (Hendriks YM et al. Gastroenterology, 2006 Feb;130:312-22; van der Klift HM et al. Hum Mutat, 2010 May;31:578-87; Suerink M et al. Genet Med, 2016 Apr;18:405-9; Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686; Post CCB et al. J Natl Cancer Inst, 2021 Sep;113:1212-1220). This mutation has also been identified in two individuals with breast cancer undergoing multi-gene panel testing (Roberts ME et al. Genet. Med. 2018 10;20:1167-1174). 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)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Lynch syndrome 4
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734561.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
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: SCV001958890.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Pathogenic
(Feb 01, 2006)
|
no assertion criteria provided
Method: literature only
|
LYNCH SYNDROME 4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030044.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
Comment on evidence:
In a family with hereditary nonpolyposis colorectal cancer (LYNCH4; 614337), Hendriks et al. (2006) identified heterozygosity for a 1882C-T transition in exon 11 of the … (more)
In a family with hereditary nonpolyposis colorectal cancer (LYNCH4; 614337), Hendriks et al. (2006) identified heterozygosity for a 1882C-T transition in exon 11 of the PMS2 gene, predicted to result in an arg628-to-ter (R628X) substitution. The mutation cosegregated with disease. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035944.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
click to load more click to collapse |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome-Associated Colorectal Carcinomas. | Helderman NC | Gastroenterology | 2023 | PMID: 36931573 |
Comprehensive immunomolecular profiling of endometrial carcinoma: A tertiary retrospective study. | Victoor J | Gynecologic oncology | 2021 | PMID: 34253388 |
Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer. | Post CCB | Journal of the National Cancer Institute | 2021 | PMID: 33693762 |
Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
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 |
Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. | Lilyquist J | Gynecologic oncology | 2017 | PMID: 28888541 |
Germline PMS2 mutation screened by mismatch repair protein immunohistochemistry of colorectal cancer in Japan. | Sugano K | Cancer science | 2016 | PMID: 27589204 |
Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome. | van der Klift HM | Human mutation | 2016 | PMID: 27435373 |
The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers. | Suerink M | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26110232 |
Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. | ten Broeke SW | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25512458 |
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 |
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 |
Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients. | van der Klift HM | Human mutation | 2010 | PMID: 20186688 |
Pediatric duodenal cancer and biallelic mismatch repair gene mutations. | Roy S | Pediatric blood & cancer | 2009 | PMID: 19283792 |
Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas. | van Puijenbroek M | Familial cancer | 2008 | PMID: 18415027 |
Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). | Hendriks YM | Gastroenterology | 2006 | PMID: 16472587 |
http://www.insight-database.org/classifications/index.html?gene=PMS2&variant=c.1882C%3ET | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs63750451 ...
HelpRecord last updated Sep 29, 2024
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.