ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.1731_1732delinsAGT (p.Arg578fs)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.1731_1732delinsAGT (p.Arg578fs)
Variation ID: 9244 Accession: VCV000009244.16
- Type and length
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Indel, 3 bp
- Location
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Cytogenetic: 7p22.1 7: 5987033-5987034 (GRCh38) [ NCBI UCSC ] 7: 6026664-6026665 (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 Oct 11, 2015 May 1, 2024 Nov 22, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- R443fs, R267fs, R387fs, R475fs, R578fs, R391fs, R472fs, R526fs
- Other names
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- Canonical SPDI
- NC_000007.14:5987032:GC:ACT
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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.
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- Comment on variant
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
5086 | 5180 |
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
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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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Pathogenic (1) |
no assertion criteria provided
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Nov 1, 2007 | RCV000009825.4 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 20, 2023 | RCV000678287.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 16, 2023 | RCV000657177.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 6, 2022 | RCV001012887.7 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001357852.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2023 | RCV003478973.1 |
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
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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
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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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Pathogenic
(Feb 04, 2020)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001343306.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant creates a frameshift and premature translation stop signal in exon 11 of the PMS2 gene. This variant is expected to result in an … (more)
This variant creates a frameshift and premature translation stop signal in exon 11 of the PMS2 gene. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in trans with a pathogenic PMS2 missense variant in two siblings with clinical features consistent with constitutional mismatch repair deficiency (PMID: 17557300). 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)
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Likely pathogenic
(Feb 20, 2018)
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criteria provided, single submitter
Method: provider interpretation, clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
paternal
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Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804344.2
First in ClinVar: Sep 07, 2018 Last updated: Dec 11, 2022 |
Comment:
This 14 year old male has a history of intellectual disability, macrocephaly, overgrowth, and hyperinsulinemia. Genetic testing to date, including exome sequencing, has not yielded … (more)
This 14 year old male has a history of intellectual disability, macrocephaly, overgrowth, and hyperinsulinemia. Genetic testing to date, including exome sequencing, has not yielded a diagnosis, but did identify a secondary finding. This variant was reported previously in a compound heterozygous state in siblings with early only cancer and a family history of colon cancer (Auclair, 2007). It is absent from gnomAD. It is expected to cause a frameshift resulting in a premature stop codon. There is no reported paternal family history of cancer. (less)
Observation 1:
Clinical Features:
Intellectual disability (present) , Macrocephalus (present) , Overgrowth (present) , Hyperinsulinemia (present) , Tall stature (present) , Obesity (present)
Age: 10-19 years
Sex: male
Secondary finding: yes
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-08-24
Testing laboratory interpretation: Likely pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Intellectual disability (present) , Macrocephalus (present) , Overgrowth (present) , Hyperinsulinemia (present) , Tall stature (present) , Obesity (present)
Age: 10-19 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-08-24
Testing laboratory interpretation: Likely pathogenic
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Pathogenic
(Nov 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223101.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PMS2 c.1731_1732delinsAGT (p.Arg578ValfsX3) 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.1731_1732delinsAGT (p.Arg578ValfsX3) 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. The variant is a multinucleotide change resulting from c.1730dupA and c.1732C>T. The variant was absent in 251352 control chromosomes. c.1731_1732delinsAGT has been reported in the literature in individuals affected with Lynch Syndrome associated cancers (example: Auclair_2007). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000778898.2
First in ClinVar: Jul 09, 2018 Last updated: Feb 07, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift 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 patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Tian et al., 2019); 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: 20531397, 22585707, 18709565, 21376568, 31054147, 17557300) (less)
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Pathogenic
(Sep 20, 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: SCV004188572.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Pathogenic
(Dec 06, 2022)
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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: SCV001173401.5
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.1731_1732delGCinsAGT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from the deletion of two nucleotides and insertion of three nucleotides … (more)
The c.1731_1732delGCinsAGT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from the deletion of two nucleotides and insertion of three nucleotides causing a translational frameshift with a predicted alternate stop codon (p.R578Vfs*3). This mutation, described as "c.1730_1731insA and c.1732C>T", was detected in trans with a second PMS2 mutation in two sisters with constitutional mismatch repair deficiency (CMMRD) (Auclair J et al. Hum. Mutat. 2007 Nov;28:1084-90). 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)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553441.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PMS2 p.Arg578Valfs*3 variant was identified in the literature in two sisters: one with severe unexplained anemia, oligodendroglioma, two synchronous colon adenocarcinomas, and a poorly … (more)
The PMS2 p.Arg578Valfs*3 variant was identified in the literature in two sisters: one with severe unexplained anemia, oligodendroglioma, two synchronous colon adenocarcinomas, and a poorly differentiated adenomatous polyp; and the other with brain angioma, colon cancer, multiple dysplastic adenomatous polyps, and endometrial cancer (Auclair 2007). This variant co-occurred with the pathogenic PMS2 variant c.137G>T (p.Ser46Ile, Auclair 2007); these sisters were likely affected with Biallelic Mismatch Repair Deficiency syndrome. The variant was also identified in dbSNP (ID: rs1057515572) as "With Pathogenic allele" and ClinVar (classified as pathogenic by GeneDx and OMIM; and as likely pathogenic by one submitter). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.1731_1732delinsAGT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 578 and leads to a premature stop codon at position 580. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(Nov 01, 2007)
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no assertion criteria provided
Method: literature only
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MISMATCH REPAIR CANCER SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030046.4
First in ClinVar: Apr 04, 2013 Last updated: Nov 28, 2020 |
Comment on evidence:
In 2 sisters with mismatch repair cancer syndrome (MMRCS4; 619101), Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the PMS2 gene: S46I … (more)
In 2 sisters with mismatch repair cancer syndrome (MMRCS4; 619101), Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the PMS2 gene: S46I (600259.0012) and a frameshift at lys577 resulting from a gene conversion event with the paralogous pseudogene PMS2CL. The converted tract was estimated to be no longer than 23 nucleotides. Both patients had colon cancer; one also had oligodendroglioma and the other also had endometrial cancer and cafe-au-lait spots. (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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Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. | Auclair J | Human mutation | 2007 | PMID: 17557300 |
Text-mined citations for rs1057515572 ...
HelpRecord last updated May 01, 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.
NCBI staff reviewed the sequence in Figure 3 of the paper by Auclair et al., 2007 (PubMed 17557300) to establish the HGVS expression for this variant.