VCV000009234.52 - ClinVar

NM_000535.7(PMS2):c.400C>T (p.Arg134Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

20 submissions

19 submitters

9 conditions

Reviewed by expert panel

Pathogenic

Sep 2013 by International …

for Lynch Syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000535.7(PMS2):c.400C>T (p.Arg134Ter)

Variation ID: 9234 Accession: VCV000009234.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 6002590 (GRCh38) [ NCBI UCSC ] 7: 6042221 (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	Aug 11, 2024	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.400C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000526.2:p.Arg134Ter	nonsense
NM_001322003.2:c.-6C>T		5 prime UTR
NM_001322004.2:c.-6C>T		5 prime UTR
NM_001322005.2:c.-6C>T		5 prime UTR
NM_001322006.2:c.400C>T	NP_001308935.1:p.Arg134Ter	nonsense
NM_001322007.2:c.82C>T	NP_001308936.1:p.Arg28Ter	nonsense
NM_001322008.2:c.82C>T	NP_001308937.1:p.Arg28Ter	nonsense
NM_001322009.2:c.-6C>T		5 prime UTR
NM_001322010.2:c.-6C>T		5 prime UTR
NM_001322011.2:c.-485C>T		5 prime UTR
NM_001322012.2:c.-485C>T		5 prime UTR
NM_001322013.2:c.-6C>T		5 prime UTR
NM_001322014.2:c.400C>T	NP_001308943.1:p.Arg134Ter	nonsense
NM_001322015.2:c.91C>T	NP_001308944.1:p.Arg31Ter	nonsense
NR_136154.1:n.487C>T		non-coding transcript variant
NC_000007.14:g.6002590G>A
NC_000007.13:g.6042221G>A
NG_008466.1:g.11517C>T
LRG_161:g.11517C>T
LRG_161t1:c.400C>T

... more HGVS ... less HGVS

Protein change

R134*, R31*, R28*

Other names

p.R134*:CGA>TGA

Canonical SPDI

NC_000007.14:6002589: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

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA012083 OMIM: 600259.0001 dbSNP: rs63750871 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	5241	5343

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.
Mismatch repair cancer syndrome 4	Pathogenic (1)	no assertion criteria provided	May 1, 2004	RCV000009815.8
Lynch syndrome	Pathogenic (4)	reviewed by expert panel	Sep 5, 2013	RCV000076872.14
Hereditary cancer-predisposing syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 10, 2024	RCV000115695.18
Lynch syndrome 4	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Nov 23, 2023	RCV000576870.8
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 18, 2024	RCV000524474.11
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV000212842.10
Mismatch repair cancer syndrome 1	Pathogenic (1)	criteria provided, single submitter	Nov 13, 2019	RCV001196700.3
Lynch syndrome 1	Pathogenic (1)	criteria provided, single submitter	Apr 2, 2020	RCV001310204.2
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162222.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 05, 2013)	reviewed by expert panel (Guidelines v1.9) Method: research	Lynch Syndrome Affected status: unknown Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000108365.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comment: Coding sequence variation resulting in a stop codon
Pathogenic (Jul 13, 2018)	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: SCV000918060.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (7) PubMed: 15845562‚ 24362816‚ 12714694‚ 21376568‚ 9488480‚ 15077197‚ 7661930 Comment: Variant summary: PMS2 c.400C>T (p.Arg134X) 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.400C>T (p.Arg134X) 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 (eg. c.697C>T, p.Gln233X; c.736_741delinsTGTGTGTGAAG, p.Pro246fsX3). The variant allele was found at a frequency of 8.2e-06 in 121392 control chromosomes. c.400C>T has been reported in the literature in individuals affected with Turcot syndrome who carry a second pathogenic variant (DeVos_2004) and in patients with Lynch Syndrome and colorectal cancer (Senter_2008, Durno_2005). These data indicate that the variant is likely to be associated with disease. Additionally, this variant was found to have a dominant negative effect in hamster fibroblast cells (Nicolaides_1998) but not in human fibroblast cells (Yamada_2003). However, the variant was found to abrogate the interaction with MLH1 (Nicolaides_1998), a known pathogenic mechanism. Six 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 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499806.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149604.18 First in ClinVar: May 17, 2014 Last updated: Jul 22, 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; Observed … (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; Observed in the heterozygous state in individuals with a personal or family history consistent with pathogenic variants in this gene (Senter 2008, Vaughn 2013, Rosty 2016); 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: 17993636, 19495563, 26720728, 29922827, 31447099, 25525159, 7661930, 15845562, 16284300, 26318770, 26270727, 7632227, 18602922, 23012243, 9488480, 16283678, 21376568, 25850602, 12714694, 26895986, 28152038, 18709565, 15077197, 30322717, 32719484, 30787465, 33087929, 35449176, 36988593) (less)
Pathogenic (Sep 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003818434.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Apr 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000686201.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 7661930‚ 15077197‚ 15845562‚ 18602922‚ 21376568‚ 26270727‚ 26318770‚ 26720728‚ 26895986 Comment: This variant changes 1 nucleotide in exon 5 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 5 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 (PMID: 18602922, 26720728, 26895986), and in an individual suspected of hereditary breast/ovarian cancer (PMID: 26270727). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 7661930, 15077197, 15845562, 21376568, 26318770). This variant has been identified in 2/276892 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 (Sep 19, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000840047.1 First in ClinVar: Jan 07, 2018 Last updated: Jan 07, 2018	Comment: The c.400C>T (p.R134) variant in the PMS2 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature … (more) The c.400C>T (p.R134) variant in the PMS2 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with constitutional mismatch repair deficiency syndrome as well as in individuals with colorectal cancer, Lynch syndrome and ovarian cancer (PMID: 15077197, 18602922, 23012243, 26681312, 26895986). The c.400C>T (p.R134*) variant in the PMS2 gene is classified as pathogenic. (less)
Pathogenic (Nov 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mismatch repair cancer syndrome 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367331.2 First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Pathogenic (Aug 19, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002530343.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The PMS2 c.400C>T (p.R134X) variant has been reported as homozygous and compound heterozygous in at least 2 individuals with constitutional mismatch repair deficiency (CMMRD) syndrome … (more) The PMS2 c.400C>T (p.R134X) variant has been reported as homozygous and compound heterozygous in at least 2 individuals with constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 26318770, 15077197). Additionally, it was also observed in patients with colorectal cancer and ovarian cancer (PMID: 18602922, 26895986, 26681312). This nonsense variant creates a premature stop codon at residue 134 of the PMS2 protein. At this location, this is predicted to cause nonsense-mediated decay and result in an absent protein (loss of function). This variant was observed in 1/35440 chromosomes in the Latino population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 9234). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (5) PubMed: 26318770‚ 15077197‚ 18602922‚ 26895986‚ 26681312
Pathogenic (May 22, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000677741.2 First in ClinVar: Jan 07, 2018 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 26895986‚ 9488480‚ 15077197
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Lynch syndrome 4 Affected status: no Allele origin: germline	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV002762834.2 First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023	Comment: PVS1, PS3, PS4_STR, PM2_SUP
Pathogenic (Apr 05, 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: SCV004019879.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Jan 19, 2023)	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: SCV000889627.3 First in ClinVar: Dec 19, 2017 Last updated: Jan 06, 2024	Publications: PubMed (14) PubMed: 25850602‚ 15077197‚ 26318770‚ 18602922‚ 26681312‚ 26895986‚ 12714694‚ 7632227‚ 9488480‚ 7661930‚ 26270727‚ 26720728‚ 35449176‚ 30322717 Comment: This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.0000071 (2/282538 chromosomes, http://gnomad.broadinstitute.org), is … (more) This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.0000071 (2/282538 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMIDs: 26895986 (2016), 18602922 (2008)), Turcot syndrome (PMIDs: 15077197 (2004), 7661930 (1995)), ovarian cancer (PMIDs: 30322717 (2018), 26720728 (2016), 26681312 (2015)), and breast cancer (PMID: 35449176 (2022)). It has also been identified in individuals with CMMRD (PMIDs: 26318770 (2015), 25850602 (2015), 15077197 (2004)). Functional studies indicate this variant causes impaired DNA mismatch repair activity (PMIDs: 9488480 (1998), 7632227 (1995)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 18, 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: SCV000166386.12 First in ClinVar: Jun 15, 2014 Last updated: Feb 14, 2024	Publications: PubMed (13) PubMed: 28492532‚ 21376568‚ 24362816‚ 15077197‚ 18602922‚ 23012243‚ 25850602‚ 26318770‚ 26681312‚ 26895986‚ 7632227‚ 9488480‚ 12714694 Comment: This sequence change creates a premature translational stop signal (p.Arg134) 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.Arg134) 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 (rs63750871, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency, colorectal cancer, Lynch syndrome, and ovarian cancer (PMID: 15077197, 18602922, 23012243, 25850602, 26318770, 26681312, 26895986). ClinVar contains an entry for this variant (Variation ID: 9234). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PMS2 function (PMID: 7632227, 9488480, 12714694). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004839977.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (9) PubMed: 7661930‚ 15077197‚ 15845562‚ 18602922‚ 21376568‚ 26270727‚ 26318770‚ 26720728‚ 26895986 Comment: This variant changes 1 nucleotide in exon 5 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 5 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 (PMID: 18602922, 26720728, 26895986), and in an individual suspected of hereditary breast/ovarian cancer (PMID: 26270727). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 7661930, 15077197, 15845562, 21376568, 26318770). This variant has been identified in 2/276892 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) Number of individuals with the variant: 4
Pathogenic (Oct 27, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000713220.4 First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024	Publications: PubMed (9) PubMed: 9488480‚ 15077197‚ 26270727‚ 26318770‚ 7632227‚ 16426742‚ 26720728‚ 7661930‚ 26895986 Comment: The p.Arg134X variant in PMS2 has been reported in at least 6 families (7 individuals) with PMS2-associated cancers (Parsons 1995 PMID: 7632227, Norquist 2016 PMID: … (more) The p.Arg134X variant in PMS2 has been reported in at least 6 families (7 individuals) with PMS2-associated cancers (Parsons 1995 PMID: 7632227, Norquist 2016 PMID: 26720728, Rosty 2016 PMID: 26895986, LaDuca 2017 PMID: 28152038, Carter 2018 PMID: 30322717) and in the compound heterozygous state in 2 families (3 individuals) with constitutional mismatch repair disease (CMMRD; De Vos 2004 PMID: 15077197, Lavoine 2015 PMID: 26318770). It has also been identified in 1/128850 of European and 1/35440 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 134, 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 vitro functional studies support an impact on protein function (Parsons 1995 PMID: 7632227, Nicolaides 1998 PMID: 9488480, Gibson 2006 PMID: 16426742). In addition, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108365.2). 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, PS3_Moderate. (less)
Pathogenic (Nov 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004207883.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 10, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000187198.9 First in ClinVar: Aug 06, 2014 Last updated: Aug 11, 2024	Publications: PubMed (8) PubMed: 15077197‚ 18602922‚ 19495563‚ 21376568‚ 26318770‚ 26720728‚ 26895986‚ 7661930 Comment: The p.R134* pathogenic mutation (also known as c.400C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at … (more) The p.R134* pathogenic mutation (also known as c.400C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 400. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been identified in multiple individuals with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome caused by biallelic PMS2 mutations (Hamilton SR et al. N. Engl. J. Med. 1995 Mar;332:839-47; De Vos M et al. Am. J. Hum. Genet. 2004 May;74:954-64; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This mutation has also been identified in multiple patients with Lynch syndrome-associated tumors that showed isolated loss of PMS2 protein expression on IHC (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). This alteration has also been detected in 1/1915 women with ovarian cancer, unselected for family history (Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90). 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 (May 01, 2004)	no assertion criteria provided Method: literature only	MISMATCH REPAIR CANCER SYNDROME 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030036.4 First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022	Publications: PubMed (3) PubMed: 7661930‚ 15077197‚ 9488480 Comment on evidence: In an 18-year-old man (family 12) with colonic adenomas, lymphoma of the rectum, glioblastoma, and multiple cafe-au-lait spots consistent with mismatch repair cancer syndrome (MMRCS4; … (more) In an 18-year-old man (family 12) with colonic adenomas, lymphoma of the rectum, glioblastoma, and multiple cafe-au-lait spots consistent with mismatch repair cancer syndrome (MMRCS4; 619101), Hamilton et al. (1995) identified a heterozygous C-to-T transition in the PMS2 gene, resulting in an arg134-to-ter (R134X) substitution. His sister had colonic carcinoma and cafe-au-lait spots. In this family, De Vos et al. (2004) identified a second mutation in the PMS2 gene: a heterozygous 2-bp deletion in exon 13, within a repeated dinucleotide (CTCT) at codon 728-729 (600259.0005). The findings were consistent with autosomal recessive inheritance of the disorder. Nicolaides et al. (1998) presented experimental evidence that the R134X substitution was sufficient to reduce mismatch repair and induce microsatellite instability in cells containing a wildtype PMS2 allele, suggesting that it could act in a dominant-negative manner. (less)
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758052.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
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Comment:

Variant summary: PMS2 c.400C>T (p.Arg134X) 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 (eg. c.697C>T, p.Gln233X; c.736_741delinsTGTGTGTGAAG, p.Pro246fsX3). The variant allele was found at a frequency of 8.2e-06 in 121392 control chromosomes. c.400C>T has been reported in the literature in individuals affected with Turcot syndrome who carry a second pathogenic variant (DeVos_2004) and in patients with Lynch Syndrome and colorectal cancer (Senter_2008, Durno_2005). These data indicate that the variant is likely to be associated with disease. Additionally, this variant was found to have a dominant negative effect in hamster fibroblast cells (Nicolaides_1998) but not in human fibroblast cells (Yamada_2003). However, the variant was found to abrogate the interaction with MLH1 (Nicolaides_1998), a known pathogenic mechanism. Six 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:

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 the heterozygous state in individuals with a personal or family history consistent with pathogenic variants in this gene (Senter 2008, Vaughn 2013, Rosty 2016); 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: 17993636, 19495563, 26720728, 29922827, 31447099, 25525159, 7661930, 15845562, 16284300, 26318770, 26270727, 7632227, 18602922, 23012243, 9488480, 16283678, 21376568, 25850602, 12714694, 26895986, 28152038, 18709565, 15077197, 30322717, 32719484, 30787465, 33087929, 35449176, 36988593)

Comment:

This variant changes 1 nucleotide in exon 5 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 (PMID: 18602922, 26720728, 26895986), and in an individual suspected of hereditary breast/ovarian cancer (PMID: 26270727). This variant has also been reported in individuals affected with constitutional mismatch repair deficiency (PMID: 7661930, 15077197, 15845562, 21376568, 26318770). This variant has been identified in 2/276892 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 c.400C>T (p.R134*) variant in the PMS2 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with constitutional mismatch repair deficiency syndrome as well as in individuals with colorectal cancer, Lynch syndrome and ovarian cancer (PMID: 15077197, 18602922, 23012243, 26681312, 26895986). The c.400C>T (p.R134*) variant in the PMS2 gene is classified as pathogenic.

Comment:

This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.0000071 (2/282538 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMIDs: 26895986 (2016), 18602922 (2008)), Turcot syndrome (PMIDs: 15077197 (2004), 7661930 (1995)), ovarian cancer (PMIDs: 30322717 (2018), 26720728 (2016), 26681312 (2015)), and breast cancer (PMID: 35449176 (2022)). It has also been identified in individuals with CMMRD (PMIDs: 26318770 (2015), 25850602 (2015), 15077197 (2004)). Functional studies indicate this variant causes impaired DNA mismatch repair activity (PMIDs: 9488480 (1998), 7632227 (1995)). Based on the available information, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg134*) 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 (rs63750871, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency, colorectal cancer, Lynch syndrome, and ovarian cancer (PMID: 15077197, 18602922, 23012243, 25850602, 26318770, 26681312, 26895986). ClinVar contains an entry for this variant (Variation ID: 9234). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PMS2 function (PMID: 7632227, 9488480, 12714694). For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Arg134X variant in PMS2 has been reported in at least 6 families (7 individuals) with PMS2-associated cancers (Parsons 1995 PMID: 7632227, Norquist 2016 PMID: 26720728, Rosty 2016 PMID: 26895986, LaDuca 2017 PMID: 28152038, Carter 2018 PMID: 30322717) and in the compound heterozygous state in 2 families (3 individuals) with constitutional mismatch repair disease (CMMRD; De Vos 2004 PMID: 15077197, Lavoine 2015 PMID: 26318770). It has also been identified in 1/128850 of European and 1/35440 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 134, 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 vitro functional studies support an impact on protein function (Parsons 1995 PMID: 7632227, Nicolaides 1998 PMID: 9488480, Gibson 2006 PMID: 16426742). In addition, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000108365.2). 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, PS3_Moderate.

Comment:

The p.R134* pathogenic mutation (also known as c.400C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 400. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration has been identified in multiple individuals with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome caused by biallelic PMS2 mutations (Hamilton SR et al. N. Engl. J. Med. 1995 Mar;332:839-47; De Vos M et al. Am. J. Hum. Genet. 2004 May;74:954-64; Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8). This mutation has also been identified in multiple patients with Lynch syndrome-associated tumors that showed isolated loss of PMS2 protein expression on IHC (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). This alteration has also been detected in 1/1915 women with ovarian cancer, unselected for family history (Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90). 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.

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
Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients.	Hu L	NPJ breast cancer	2022	PMID: 35449176
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort.	Rosty C	BMJ open	2016	PMID: 26895986
Inherited Mutations in Women With Ovarian Carcinoma.	Norquist BM	JAMA oncology	2016	PMID: 26720728
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.	Lavoine N	Journal of medical genetics	2015	PMID: 26318770
Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment.	Desmond A	JAMA oncology	2015	PMID: 26270727
An Unusual Case of Constitutional Mismatch Repair Deficiency Syndrome With Anaplastic Ganglioglioma, Colonic Adenocarcinoma, Osteosarcoma, Acute Myeloid Leukemia, and Signs of Neurofibromatosis Type 1: Case Report.	Daou B	Neurosurgery	2015	PMID: 25850602
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
The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene.	Vaughn CP	Genes, chromosomes & cancer	2013	PMID: 23012243
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
Anaplastic oligoastrocytoma in Turcot syndrome.	Baehring J	Journal of neuro-oncology	2009	PMID: 19495563
The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.	Senter L	Gastroenterology	2008	PMID: 18602922
Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance.	Gibson SL	Cancer letters	2006	PMID: 16426742
Family history and molecular features of children, adolescents, and young adults with colorectal carcinoma.	Durno C	Gut	2005	PMID: 15845562
Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.	De Vos M	American journal of human genetics	2004	PMID: 15077197
Variation in the extent of microsatellite instability in human cell lines with defects in different mismatch repair genes.	Yamada NA	Mutagenesis	2003	PMID: 12714694
A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype.	Nicolaides NC	Molecular and cellular biology	1998	PMID: 9488480
The molecular basis of Turcot's syndrome.	Hamilton SR	The New England journal of medicine	1995	PMID: 7661930
Mismatch repair deficiency in phenotypically normal human cells.	Parsons R	Science (New York, N.Y.)	1995	PMID: 7632227
http://www.insight-database.org/classifications/index.html?gene=PMS2&variant=c.400C%3ET	-	-	-	-
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Text-mined citations for rs63750871 ...

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.400C>T (p.Arg134Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750871 ...