ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2523G>A (p.Trp841Ter)
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.
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(2); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.2523G>A (p.Trp841Ter)
Variation ID: 127786 Accession: VCV000127786.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5973465 (GRCh38) [ NCBI UCSC ] 7: 6013096 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 17, 2018 May 1, 2024 Sep 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.2523G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Trp841Ter nonsense NM_001322003.2:c.2118G>A NP_001308932.1:p.Trp706Ter nonsense NM_001322004.2:c.2118G>A NP_001308933.1:p.Trp706Ter nonsense NM_001322005.2:c.2118G>A NP_001308934.1:p.Trp706Ter nonsense NM_001322006.2:c.2367G>A NP_001308935.1:p.Trp789Ter nonsense NM_001322007.2:c.2205G>A NP_001308936.1:p.Trp735Ter nonsense NM_001322008.2:c.2205G>A NP_001308937.1:p.Trp735Ter nonsense NM_001322009.2:c.2151G>A NP_001308938.1:p.Trp717Ter nonsense NM_001322010.2:c.1962G>A NP_001308939.1:p.Trp654Ter nonsense NM_001322011.2:c.1590G>A NP_001308940.1:p.Trp530Ter nonsense NM_001322012.2:c.1590G>A NP_001308941.1:p.Trp530Ter nonsense NM_001322013.2:c.1950G>A NP_001308942.1:p.Trp650Ter nonsense NM_001322014.2:c.2556G>A NP_001308943.1:p.Trp852Ter nonsense NM_001322015.2:c.2214G>A NP_001308944.1:p.Trp738Ter nonsense NR_136154.1:n.2567G>A non-coding transcript variant NC_000007.14:g.5973465C>T NC_000007.13:g.6013096C>T NG_008466.1:g.40642G>A LRG_161:g.40642G>A LRG_161t1:c.2523G>A - Protein change
- W841*, W530*, W654*, W717*, W650*, W706*, W738*, W789*, W852*, W735*
- Other names
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- Canonical SPDI
- NC_000007.14:5973464:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00174
The Genome Aggregation Database (gnomAD), exomes 0.00039
Exome Aggregation Consortium (ExAC) 0.00092
1000 Genomes Project 30x 0.00172
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5155 | 5249 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV000586246.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 25, 2023 | RCV000987818.3 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 11, 2023 | RCV002256045.6 |
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
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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
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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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Uncertain significance
(Aug 27, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530314.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PMS2 c.2523G>A (p.W841X) variant has been reported in heterozygosity in at least 4 individuals with breast cancer, Cowden-like syndrome, or glioma (PMID: 24549055, 26689913, … (more)
The PMS2 c.2523G>A (p.W841X) variant has been reported in heterozygosity in at least 4 individuals with breast cancer, Cowden-like syndrome, or glioma (PMID: 24549055, 26689913, 29335925, 29684080). It was also identified in an individual undergoing genetic testing but was not reported by authors due to the relatively high population frequency of the variant (PMID: 30122538). As this variant is not predicted to cause nonsense-mediated decay, the protein is expected to be truncated. This variant was observed in 91/14212 chromosomes in the African population, with 3 homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org). However, the frequency may not be reliable due to PMS2 pseudogene interference. The variant has been reported in ClinVar (Variation ID: 127786). The overall evidence is inconsistent with ACMG/AMP requirements for a classification of benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697349.8
First in ClinVar: Mar 17, 2018 Last updated: Oct 04, 2023 |
Comment:
Variant summary: PMS2 c.2523G>A (p.Trp841X) results in a premature termination codon in the last exon of the PMS2 mRNA, which raises the possibility of it … (more)
Variant summary: PMS2 c.2523G>A (p.Trp841X) results in a premature termination codon in the last exon of the PMS2 mRNA, which raises the possibility of it escaping nonsense mediated decay and causing a truncation of the last 22 amino acids (Trp841-Asn862) of the PMS2 protein, which might affect the MLH1 dimerization domain (PMID 10037723). This region also contains conserved residues that are predicted to be functionally important for metal ion binding, and appear required for normal MMR activity in mutation assays (PMID 18619468). Another variant (c.2521delT (p.Trp841GlyfsX10)) that results in a frameshift at the same codon, has been classified as pathogenic by our laboratory. The c.2523G>A (p.Trp841X) allele was found at a frequency of 0.00039 in 180738 control chromosomes, predominantly at a frequency of 0.006 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes, which could suggest a benign role. However, the region is highly homologous to PMS2 pseudogenes, and the technology utilized for this dataset does not rule out pseudogene interference, therefore these data might not be reliable for assessing variant frequency. c.2523G>A has been reported in the literature in individuals affected with HBOC and other tumor phenotypes (e.g. Castera_2014, Lu_2015, Fostira_2018, Guindalini_2022). Since none of these reports ruled out PMS2 pseudogene interference, these reports do not provide unequivocal conclusions about an association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Of note however, in functional studies performed on lymphoblastoid cell lines (LCLs) derived from a patient carrying a similar truncating variant (c.2521delT (p.Trp841GlyfsX10)) in homozygosity, MSI (microsatellite instability) and tolerance to methylating agents could be demonstrated (PMID: 26116798). These results suggest that truncation of the last 22 amino acids might have functional importance. The following publications have been ascertained in the context of this evaluation (PMID: 24549055, 26689913, 29335925, 35264596). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, classifying it as uncertain significance (n=4) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001137276.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(May 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046995.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Pathogenic
(Sep 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004187760.1
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.
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002742057.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.W841* pathogenic mutation (also known as c.2523G>A), located in coding exon 15 of the PMS2 gene, results from a G to A substitution at … (more)
The p.W841* pathogenic mutation (also known as c.2523G>A), located in coding exon 15 of the PMS2 gene, results from a G to A substitution at nucleotide position 2523. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of PMS2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 22 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data; Kosinski J et al. J. Mol. Biol., 2008 Oct;382:610-27). This alteration has been identified by multigene panel testing for hereditary cancer in a patient with male breast cancer and in a female patient diagnosed with breast cancer at the age of 41 who had a family history of breast and prostate cancer (Castéra L et al. Eur. J. Hum. Genet., 2014 Nov;22:1305-13; Fostira F et al. Breast Cancer Res. Treat., 2018 May;169:105-113). Another truncating pathogenic mutation located downstream from this alteration, p.W841Gfs*10, has also been identified in several individuals whose colorectal tumors demonstrated isolated loss of PMS2 expression on immunohistochemistry (IHC) (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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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 |
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Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. | Guindalini RSC | Scientific reports | 2022 | PMID: 35264596 |
Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. | Abou Tayoun AN | Human mutation | 2018 | PMID: 30192042 |
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot. | Sapp JC | American journal of human genetics | 2018 | PMID: 30122538 |
Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. | Yehia L | PLoS genetics | 2018 | PMID: 29684080 |
Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer. | Fostira F | Breast cancer research and treatment | 2018 | PMID: 29335925 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. | Castéra L | European journal of human genetics : EJHG | 2014 | PMID: 24549055 |
The PMS2 subunit of human MutLalpha contains a metal ion binding domain of the iron-dependent repressor protein family. | Kosinski J | Journal of molecular biology | 2008 | PMID: 18619468 |
Text-mined citations for rs587780057 ...
HelpRecord last updated Jun 02, 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.