VCV000234508.41 - ClinVar

NM_000535.7(PMS2):c.631C>T (p.Arg211Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000535.7(PMS2):c.631C>T (p.Arg211Ter)

Variation ID: 234508 Accession: VCV000234508.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 5999182 (GRCh38) [ NCBI UCSC ] 7: 6038813 (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 19, 2017	Jun 17, 2024	Feb 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.631C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000526.2:p.Arg211Ter	nonsense
NM_001322003.2:c.226C>T	NP_001308932.1:p.Arg76Ter	nonsense
NM_001322004.2:c.226C>T	NP_001308933.1:p.Arg76Ter	nonsense
NM_001322005.2:c.226C>T	NP_001308934.1:p.Arg76Ter	nonsense
NM_001322006.2:c.631C>T	NP_001308935.1:p.Arg211Ter	nonsense
NM_001322007.2:c.313C>T	NP_001308936.1:p.Arg105Ter	nonsense
NM_001322008.2:c.313C>T	NP_001308937.1:p.Arg105Ter	nonsense
NM_001322009.2:c.226C>T	NP_001308938.1:p.Arg76Ter	nonsense
NM_001322010.2:c.226C>T	NP_001308939.1:p.Arg76Ter	nonsense
NM_001322011.2:c.-303C>T		5 prime UTR
NM_001322012.2:c.-303C>T		5 prime UTR
NM_001322013.2:c.133-1759C>T		intron variant
NM_001322014.2:c.631C>T	NP_001308943.1:p.Arg211Ter	nonsense
NM_001322015.2:c.322C>T	NP_001308944.1:p.Arg108Ter	nonsense
NR_136154.1:n.718C>T		non-coding transcript variant
NC_000007.14:g.5999182G>A
NC_000007.13:g.6038813G>A
NG_008466.1:g.14925C>T
LRG_161:g.14925C>T
LRG_161t1:c.631C>T

... more HGVS ... less HGVS

Protein change

R211*, R76*, R105*, R108*

Other names

Canonical SPDI

NC_000007.14:5999181:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA050695 dbSNP: rs760228510 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.
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.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 29, 2022	RCV000222317.8
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 10, 2024	RCV000473579.12
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jul 6, 2022	RCV000568505.8
Lynch syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 2, 2023	RCV001174885.3
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003165579.2
Lynch syndrome 4	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 2, 2024	RCV003454666.3
Mismatch repair cancer syndrome 4	Pathogenic (1)	criteria provided, single submitter	Jul 20, 2023	RCV003315238.3

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 (Jul 29, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279402.11 First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023	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; Not … (more) 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Identified in several individuals with colorectal cancer whose tumors demonstrated absence of PMS2 expression on immunohistochemistry or met Bethesda criteria (Buchanan et al., 2017; Ohmoto et al., 2018; Jiang et al., 2019; Wang et al., 2020); This variant is associated with the following publications: (PMID: 27273229, 28975465, 30521064, 29667044, 31992580, 30787465) (less)
Pathogenic (Jan 10, 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: SCV000552000.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 28492532‚ 21376568‚ 24362816‚ 27273229 Comment: This sequence change creates a premature translational stop signal (p.Arg211) 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.Arg211) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 27273229). ClinVar contains an entry for this variant (Variation ID: 234508). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 06, 2022)	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: SCV000670743.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Comment: The p.R211* pathogenic mutation (also known as c.631C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at … (more) The p.R211* pathogenic mutation (also known as c.631C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 631. This changes the amino acid from an arginine to a stop codon within coding exon 6. 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 (Feb 13, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001338298.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (4) PubMed: 27273229‚ 29667044‚ 30521064‚ 28975465 Comment: Variant summary: PMS2 c.631C>T (p.Arg211X) 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.631C>T (p.Arg211X) 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 was absent in 251494 control chromosomes. c.631C>T has been reported in the literature in individuals affected with colorectal cancer, pancreatic ductal adenocarcinoma, or breast cancer (Jiang_2019, Buchanan_2016, Ohmoto_2018, Siraj_2017). These data indicate that the variant is likely to be associated with disease. Four 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)
Pathogenic (Apr 05, 2021)	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: SCV000686222.2 First in ClinVar: Feb 19, 2018 Last updated: Jan 08, 2022	Comment: This variant changes 1 nucleotide in exon 6 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 6 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 27273229, 28975465, 29667044, 30521064) with one individual also affected with pancreatic cancer (PMID: 29667044). This variant has not been identified 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 (Jul 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mismatch repair cancer syndrome 4 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center Accession: SCV004014850.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023
Pathogenic (Sep 19, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004187710.1 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 (Jan 29, 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: SCV004219018.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (9) PubMed: 33471991‚ 30521064‚ 29667044‚ 28975465‚ 27273229‚ 31992580‚ 31101557‚ 30729418‚ 31118792 Comment: This nonsense variant causes the premature termination of PMS2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the … (more) This nonsense variant causes the premature termination of PMS2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome and breast cancer, as well as in unaffected controls (PMIDs: 33471991 (2021), 31992580 (2020), 31118792 (2019), 31101557 (2019), 30729418 (2019), 30521064 (2019), 29667044 (2018), 28975465 (2017), 27273229 (2017)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003818412.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Feb 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847560.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Arg211X variant in PMS2 has been reported in at least 4 individuals affected with colorectal cancer (Buchanan 2017 PMID: 27273229, Siraj 2017 PMID: 28975465, … (more) The p.Arg211X variant in PMS2 has been reported in at least 4 individuals affected with colorectal cancer (Buchanan 2017 PMID: 27273229, Siraj 2017 PMID: 28975465, Ohmoto 2018 PMID: 29667044, Jiang 2019 PMID: 30521064); one of those individuals was also affected with pancreatic cancer (Ohmoto 2018 PMID: 29667044). This variant has also been reported in ClinVar (Variation ID 234508) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 211, 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PVS1. (less)
Pathogenic (Feb 02, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205343.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758157.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
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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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Identified in several individuals with colorectal cancer whose tumors demonstrated absence of PMS2 expression on immunohistochemistry or met Bethesda criteria (Buchanan et al., 2017; Ohmoto et al., 2018; Jiang et al., 2019; Wang et al., 2020); This variant is associated with the following publications: (PMID: 27273229, 28975465, 30521064, 29667044, 31992580, 30787465)

Comment:

This sequence change creates a premature translational stop signal (p.Arg211*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 27273229). ClinVar contains an entry for this variant (Variation ID: 234508). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.R211* pathogenic mutation (also known as c.631C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 631. This changes the amino acid from an arginine to a stop codon within coding exon 6. 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:

Variant summary: PMS2 c.631C>T (p.Arg211X) 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 was absent in 251494 control chromosomes. c.631C>T has been reported in the literature in individuals affected with colorectal cancer, pancreatic ductal adenocarcinoma, or breast cancer (Jiang_2019, Buchanan_2016, Ohmoto_2018, Siraj_2017). These data indicate that the variant is likely to be associated with disease. Four 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:

This variant changes 1 nucleotide in exon 6 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 27273229, 28975465, 29667044, 30521064) with one individual also affected with pancreatic cancer (PMID: 29667044). This variant has not been identified 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:

This nonsense variant causes the premature termination of PMS2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome and breast cancer, as well as in unaffected controls (PMIDs: 33471991 (2021), 31992580 (2020), 31118792 (2019), 31101557 (2019), 30729418 (2019), 30521064 (2019), 29667044 (2018), 28975465 (2017), 27273229 (2017)). Based on the available information, this variant is classified as pathogenic.

Comment:

The p.Arg211X variant in PMS2 has been reported in at least 4 individuals affected with colorectal cancer (Buchanan 2017 PMID: 27273229, Siraj 2017 PMID: 28975465, Ohmoto 2018 PMID: 29667044, Jiang 2019 PMID: 30521064); one of those individuals was also affected with pancreatic cancer (Ohmoto 2018 PMID: 29667044). This variant has also been reported in ClinVar (Variation ID 234508) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 211, 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PVS1.

Germline Functional Evidence

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

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
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
Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome.	Wang Q	Journal of medical genetics	2020	PMID: 31992580
Mutation spectrum of germline cancer susceptibility genes among unselected Chinese colorectal cancer patients.	Gong R	Cancer management and research	2019	PMID: 31118792
Outcomes of disease-specific next-generation sequencing gene panel testing in adolescents and young adults with colorectal cancer.	Mork ME	Cancer genetics	2019	PMID: 31101557
Implementation of a Systematic Tumor Screening Program for Lynch Syndrome in an Integrated Health Care Setting.	Clarke EV	Familial cancer	2019	PMID: 30729418
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
Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines.	Ohmoto A	Journal of gastroenterology	2018	PMID: 29667044
Expanding the spectrum of germline variants in cancer.	Siraj AK	Human genetics	2017	PMID: 28975465
Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts.	Buchanan DD	Journal of gastroenterology and hepatology	2017	PMID: 27273229
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
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Text-mined citations for rs760228510 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000535.7(PMS2):c.631C>T (p.Arg211Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs760228510 ...