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NM_000535.7(PMS2):c.2521del (p.Trp841fs)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(2);Pathogenic(2);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
6 (Most recent: Mar 31, 2021)
Last evaluated:
Jun 1, 2020
Accession:
VCV000265586.8
Variation ID:
265586
Description:
1bp deletion
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NM_000535.7(PMS2):c.2521del (p.Trp841fs)

Allele ID
259868
Variant type
Deletion
Variant length
1 bp
Cytogenetic location
7p22.1
Genomic location
7: 5973467 (GRCh38) GRCh38 UCSC
7: 6013098 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000007.13:g.6013098del
NC_000007.14:g.5973467del
NM_000535.7:c.2521del MANE Select NP_000526.2:p.Trp841fs frameshift
... more HGVS
Protein change
W530fs, W706fs, W717fs, W735fs, W738fs, W852fs, W650fs, W789fs, W841fs, W654fs
Other names
-
Canonical SPDI
NC_000007.14:5973466:A:
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA10588430
dbSNP: rs886039646
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 1 criteria provided, single submitter Jun 1, 2020 RCV000552542.4
Pathogenic 1 criteria provided, single submitter Dec 13, 2018 RCV000564745.1
Likely pathogenic 1 criteria provided, single submitter Dec 17, 2019 RCV000722118.2
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Sep 11, 2017 RCV000255351.3
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
PMS2 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
3057 3122

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jul 27, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
Accession: SCV000884400.1
Submitted: (Oct 10, 2018)
Evidence details
Comment:
The PMS2 c.2521delT;p.Trp841fs variant has been published at least once in an individual with suspected constitutional mismatch repair deficiency syndrome, who also carried an additional … (more)
Likely pathogenic
(Sep 11, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000322576.8
Submitted: (Jan 29, 2019)
Evidence details
Comment:
This deletion of one nucleotide in PMS2 is denoted c.2521delT at the cDNA level and p.Trp841GlyfsX10 (W841GfsX10) at the protein level. The normal sequence, with … (more)
Likely pathogenic
(Dec 17, 2019)
criteria provided, single submitter
Method: clinical testing
Turcot syndrome
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697352.3
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (4)
Comment:
Variant summary: PMS2 c.2521delT (p.Trp841GlyfsX10) results in a premature termination codon in the last exon of the PMS2 mRNA, predicted to cause a truncation and … (more)
Pathogenic
(Dec 13, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000670737.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (1)
Comment:
The c.2521delT pathogenic mutation, located in coding exon 15 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 2521, causing … (more)
Pathogenic
(Jun 01, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000625623.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (6)
Comment:
This sequence change results in a premature translational stop signal in the PMS2 gene (p.Trp841Glyfs*10). While this is not anticipated to result in nonsense mediated … (more)
Likely pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: unknown
Department of Pathology and Laboratory Medicine,Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554334.1
Submitted: (Mar 31, 2021)
Evidence details
Comment:
The PMS2 p.Trp841Glyfs*10 variant was not identified in the literature however it was identified in dbSNP (ID: rs886039646) as “With Pathogenic allele”, ClinVar (classified with … (more)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Effective Immunotherapy of Glioblastoma in an Adolescent with Constitutional Mismatch Repair-Deficiency Syndrome. Pavelka Z Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti 2019 PMID: 30764633
Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome. Maletzki C Molecular carcinogenesis 2017 PMID: 28218421
[Retrospective NGS Study in High-risk Hereditary Cancer Patients at Masaryk Memorial Cancer Institute]. Macháčková E Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti 2016 PMID: 26691941
Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. Bodo S Gastroenterology 2015 PMID: 26116798
Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair. Kosinski J Human mutation 2010 PMID: 20533529
Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair. Mohd AB DNA repair 2006 PMID: 16338176
The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. Guerrette S The Journal of biological chemistry 1999 PMID: 10037723

Text-mined citations for rs886039646...

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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 Jun 14, 2021