ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.137G>T (p.Ser46Ile)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.137G>T (p.Ser46Ile)
Variation ID: 9245 Accession: VCV000009245.90
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 6005918 (GRCh38) [ NCBI UCSC ] 7: 6045549 (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 Dec 6, 2014 Oct 8, 2024 Jun 21, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.137G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Ser46Ile missense NM_001322003.2:c.-269G>T 5 prime UTR NM_001322004.2:c.-242-1860G>T intron variant NM_001322005.2:c.-269G>T 5 prime UTR NM_001322006.2:c.137G>T NP_001308935.1:p.Ser46Ile missense NM_001322007.2:c.-79G>T 5 prime UTR NM_001322008.2:c.-52-1860G>T intron variant NM_001322009.2:c.-269G>T 5 prime UTR NM_001322010.2:c.-242-1860G>T intron variant NM_001322011.2:c.-748G>T 5 prime UTR NM_001322012.2:c.-748G>T 5 prime UTR NM_001322013.2:c.-269G>T 5 prime UTR NM_001322014.2:c.137G>T NP_001308943.1:p.Ser46Ile missense NM_001322015.2:c.-348G>T 5 prime UTR NR_136154.1:n.224G>T non-coding transcript variant NC_000007.14:g.6005918C>A NC_000007.13:g.6045549C>A NG_008466.1:g.8189G>T NG_050738.1:g.1668C>A LRG_161:g.8189G>T LRG_161t1:c.137G>T P54278:p.Ser46Ile - Protein change
- S46I
- Other names
- p.S46I:AGT>ATT
- Canonical SPDI
- NC_000007.14:6005917:C:A
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00013
The Genome Aggregation Database (gnomAD) 0.00018
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 | ||
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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. |
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PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5240 | 5342 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000009826.21 | |
Likely pathogenic (5) |
reviewed by expert panel
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Jun 21, 2019 | RCV000076807.31 | |
Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2024 | RCV000056324.32 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000115657.26 | |
Pathogenic/Likely pathogenic (16) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2024 | RCV000200994.55 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000524432.18 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 18, 2016 | RCV000722017.10 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 1, 2013 | RCV001267878.10 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001353458.10 | |
Likely pathogenic (2) |
criteria provided, single submitter
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May 1, 2021 | RCV001804723.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 2, 2022 | RCV001797999.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 28, 2022 | RCV002476951.8 | |
PMS2-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jul 12, 2024 | RCV003390667.6 |
PMS2-related cancer disorders
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Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335023.1 |
Pathogenic (1) |
criteria provided, single submitter
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Nov 15, 2023 | RCV004555831.1 | |
Inherited MMR deficiency (Lynch syndrome)
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Pathogenic (1) |
criteria provided, single submitter
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Jun 14, 2024 | RCV004691720.1 |
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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. |
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Likely pathogenic
(Jun 21, 2019)
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reviewed by expert panel
Method: curation
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Lynch syndrome
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108292.4
First in ClinVar: Dec 19, 2013 Last updated: Oct 01, 2019 |
Comment:
>2 MSI tumours; deficient protein function inferred from 2 independent assays
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Likely pathogenic
(Apr 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: yes
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Study: Clinvar_gadteam_Clinical_exome_analysis_3
Accession: SCV000803859.1 First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
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Pathogenic
(Nov 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918033.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: The PMS2 c.137G>T (p.Ser46Ile) variant involves the alteration of a conserved nucleotide that results in a missense change within the nucleotide binding pocket … (more)
Variant summary: The PMS2 c.137G>T (p.Ser46Ile) variant involves the alteration of a conserved nucleotide that results in a missense change within the nucleotide binding pocket of the ATPase domain (Borras 2013). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies have shown the variant to cause deficient MMR activity (Borras 2013, Drost 2013, van der Klift 2016). This variant was found in 47/271742 control chromosomes (in gnomAD and publication controls), however the technology utilized for the gnomAD dataset does not rule out pseudogene interference and thus this data cannot be relied upon. This variant has been reported in several patients/families with Lynch syndrome-associated cancers (in many cases isolated loss of PMS2 was detected in the tumors) as well as in patients with constitutional MMR deficiency (CMMR-D) syndrome who also have a second pathogenic PMS2 mutation (in many of these cases PMS2 loss in normal tissues was documented) (Clendenning 2006, Senter 2008, Herkert_2011, Tomsic 2013, Borras 2013, van der Klift 2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Likely pathogenic
(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: SCV001137331.1
First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020 |
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Likely pathogenic
(Feb 05, 2016)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450303.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 3
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Likely pathogenic
(Sep 24, 2018)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002072174.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.137G>T, in exon 2 that results in an amino acid change, p.Ser46Ile. The p.Ser46Ile … (more)
DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.137G>T, in exon 2 that results in an amino acid change, p.Ser46Ile. The p.Ser46Ile change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Ser46Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL), and has been described in the EXAC database with a low population frequency of 0.013% (dbSNP rs121434629). This particular amino acid change has been described in the literature in the homozygous and compound heterozygous states in patients with autosomal recessive constitutional mismatch repair deficiency syndrome (PMIDs: 21204794, 16144131, 21376568). This variant was also reported in 2 members of a family affected with lynch syndrome associated colorectal and skin tumors, and bladder cancer (PMID: 23709753). In vitro functional assays demonstrate decreased mismatch repair activity for the Ser46Ile variant compared to wild type (PMID: 23709753). (less)
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Pathogenic
(Mar 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Mismatch repair cancer syndrome 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894431.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604885.6
First in ClinVar: Sep 30, 2017 Last updated: Mar 04, 2023 |
Comment:
The PMS2 c.137G>T; p.Ser46Ile variant (rs121434629) is published in the literature in individuals and families with Lynch syndrome-associated cancers and constitutional mismatch repair-deficiency (Auclair 2007, … (more)
The PMS2 c.137G>T; p.Ser46Ile variant (rs121434629) is published in the literature in individuals and families with Lynch syndrome-associated cancers and constitutional mismatch repair-deficiency (Auclair 2007, Borras 2013, Jackson 2008, Senter 2008, Tosmic 2013). This variant is reported in ClinVar (Variation ID: 9245) and is found in the Latino population with an overall allele frequency of 0.03% (11/35,326 alleles) in the Genome Aggregation Database. Several individuals with constitutional mismatch repair-deficiency carried this variant in trans to a pathogenic PMS2 variant (Auclair 2007, Jackson 2008, Senter 2008), including another variant at the same codon, p.Ser46Asn, observed in two affected individuals (Jackson 2008, Senter 2008). The serine at codon 46 is highly conserved and both the p.Ser46Ile and p.Ser46Asn variants exhibit less than 10% of wild-type activity in mismatch repair in vitro assays (Borras 2013, Drost 2013). Based on available information, this variant is considered to be pathogenic. References: Auclair J et al. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat. 2007 Nov;28(11):1084-90. PMID: 17557300 Borras E et al. Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. J Med Genet. 2013 Aug;50(8):552-63. PMID: 23709753 Drost M et al. Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene. Hum Mutat. 2013 Nov;34(11):1477-80. PMID: 24027009 Jackson CC et al. Cafe-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2. Pediatr Blood Cancer. 2008 Jun;50(6):1268-70. PMID: 18273873 Senter L et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008 Aug;135(2):419-28. PMID: 18602922 Tomsic J et al. Recurrent and founder mutations in the PMS2 gene. Clin Genet. 2013 Mar;83(3):238-43. PMID: 22577899 (less)
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Pathogenic
(Apr 30, 2020)
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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: SCV000149566.17
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Observed in individuals in the heterozygous state with a personal or family history consistent with pathogenic variants in this gene and reported as a Caucasian … (more)
Observed in individuals in the heterozygous state with a personal or family history consistent with pathogenic variants in this gene and reported as a Caucasian founder variant (Nakagawa 2004, Agostini 2005, Clendenning 2006, Auclair 2007, Jackson 2008, Senter 2008, Van der Klift 2010, Herkert 2011, Leenen 2011, Tomsic 2013, Lavoine 2015, Ponti 2015, ten Broeke 2015, Heath 2016, van der Klift 2016, Nowak 2017, Rengifo-Cam 2017); Published functional studies demonstrate a damaging effect: in vitro cell-free complementation assays showed deficient mismatch repair activity as well as reduced PMS2 expression (Nakagawa 2004, Borras 2013, Drost 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25871621, 20186688, 25980754, 26110232, 25345868, 25512458, 28286799, 28528518, 25194673, 22949387, 15256438, 16144131, 16619239, 17557300, 18273873, 18602922, 21376568, 21204794, 22577899, 26318770, 26808570, 27435373, 27863258, 30155321, 23709753, 24027009, 11574484, 24055113, 25637381, 21239990, 26940435, 26143115, 26895986, 26976419, 27433846, 26681312, 28514183, 28365877, 26845104, 28873162, 28904067, 28125078, 27806231, 28152038, 28449805, 26556299, 30013564, 25186627, 29875428, 30702970, 30612635, 31857677, 32060697, 31992580, 31447099, 31433215, 31948886, 31589614, 32719484, 32571878, 33258288, 32634176, 33504652) (less)
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Likely pathogenic
(May 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042783.2
First in ClinVar: Jan 01, 2022 Last updated: Mar 11, 2023 |
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Likely pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009116.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Apr 05, 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: SCV004019868.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26116798, 26318770, 17557300, 32642664, 30608896]. … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26116798, 26318770, 17557300, 32642664, 30608896]. Functional studies indicate this variant impacts protein function [PMID: 24027009, 23709753, 27435373, 30608896, 17557300]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Apr 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601815.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in multiple families with Lynch syndrome as well as in individuals with biallelic pathogenic variants who … (more)
In the published literature, this variant has been reported in multiple families with Lynch syndrome as well as in individuals with biallelic pathogenic variants who have been diagnosed with constitutional mismatch repair deficiency (CMMR-D) syndrome (PMIDs: 30702970 (2019), 21239990 (2011), 20205264 (2010), 16144131 (2005)). Additionally, functional studies have shown this variant causes significantly reduced DNA mismatch repair activity in vitro (PMID: 23709753 (2013)). The frequency of this variant in the general population, 0.00031 (11/35326 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018884.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004842155.1
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)
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Comment:
The c.137G>T (p.Ser46Ile) variant in the PMS2 gene is located on the exon 2 and is predicted to replace serine with isoleucine at codon 46 … (more)
The c.137G>T (p.Ser46Ile) variant in the PMS2 gene is located on the exon 2 and is predicted to replace serine with isoleucine at codon 46 (p.Ser46Ile). The variant has been reported in more than 10 unrelated individuals affected with Lynch syndrome in heterozygous state (PMID: 18602922, 27435373, 21204794, 32634176). A different missense variant affecting the same amino acid (p.Ser46Asn) has been interpreted as pathogenic (ClinVar ID: 91301). The variant has been reported in more than 10 unrelated individuals with constitutional mismatch repair-deficiency (CMMRD) syndrome in homozygous or compound heterozygous states (PMID: 21204794, 32642664, 26318770). The variant was detected in trans with other pathogenic variants (p.Pro246fs, p.Arg578fs) in individuals with CMMRD (ClinVar ID: 91366, 9244, PMID: 21204794, 32642664). Experimental studies showed this variant resulted in impaired mismatch repair activity and negative functional impact on the protein (PMID: 23709753, 24027009). The variant is reported in ClinVar (ID: 9245). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.939). Therefore, the c.137G>T (p.Ser46Ile) variant of PMS2 has been classified as pathogenic. (less)
Number of individuals with the variant: 36
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Pathogenic
(Mar 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271259.4
First in ClinVar: May 29, 2016 Last updated: Apr 20, 2024 |
Comment:
The p.Ser46Ile variant in PMS2 has been described as a founder variant for Lynch syndrome in Caucasians (Ponti 2015 PMID:25345868, Tomsic 2013 PMID:22577899). It has … (more)
The p.Ser46Ile variant in PMS2 has been described as a founder variant for Lynch syndrome in Caucasians (Ponti 2015 PMID:25345868, Tomsic 2013 PMID:22577899). It has been reported in the heterozygous state in >15 individuals with Lynch syndrome-associated cancers, where the tumors showed microsatellite instability and loss of PMS2 expression in some individuals (Borras 2013 PMID:23709753, Clendenning 2006 PMID:16619239, Cock-Rada 2017 PMID:28528518, Haraldsdottir 2013 PMID:25194673, Le 2017 PMID:28596308, Nakagawa 2004 PMID:15256438, Pritchard 2016 PMID:27433846, Senter 2008 PMID:18602922, Tomsic 2013 PMID:22577899, ClinVar: Variation ID 9245). This variant has also been reported in the biallelic state (homozygous or compound heterozygous with a second pathogenic variant) in at least 9 individuals with constitutional mismatch repair deficiency syndrome (CMMRD) and segregated with disease in at least 3 affected relatives from at least 2 families (Auclair 2007 PMID:17557300, Borras 2013 PMID:23709753, Giunti 2009 PMID:19156169, Herkert 2011 PMID:21376568). Normal and tumor tissue from some individuals with CMMRD showed loss of expression of PMS2 (Agostini 2005 PMID:16144131, Auclair 2007 PMID:17557300, Bodo 2015 PMID:26116798, Giunti 2009 PMID:19156169, Herkert 2011 PMID:21376568, Jackson 2008 PMID:18273873, Lavoine 2015 PMID:26318770, Pastrello 2011 PMID:21239990, Stark 2014 PMID:24897087). Additionally, some relatives who were heterozygous carriers of this variant were clinically unaffected, suggesting reduced penetrance. In vitro functional studies provide some evidence that the p.Ser46Ile variant may impact protein function (Borras 2013 PMID:23709753, Drost 2013 PMID:24027009, Nakagawa 2004 PMID:15256438). This variant has been identified in 0.04% (416/1179868) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the frequency and penetrance of PMS2-associated Lynch syndrome. Computational prediction tools and conservation analysis suggest that the p.Ser46Ile variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome (ACMG/AMP Criteria applied: PS3; PS4; PP1; PP3) and for autosomal recessive CMMRD (ACMG/AMP Criteria applied: PM3_Very_strong; PS3; PP1; PP3). (less)
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Pathogenic
(Nov 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 9
Dilated cardiomyopathy 1G
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005045097.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Comment:
The PMS2 c.137G>T (p.Ser46Ile) variant has been reported in a number individuals affected with Lynch syndrome (Borras E et al., PMID: 23709753; Senter L et … (more)
The PMS2 c.137G>T (p.Ser46Ile) variant has been reported in a number individuals affected with Lynch syndrome (Borras E et al., PMID: 23709753; Senter L et al., PMID: 18602922; Tosmic J et al., PMID: 22577899) or mismatch repair cancer syndrome (Agostini M et al., PMID: 16144131; Herkert JC et al., PMID: 21376568; Leenen CHM et al., PMID: 21204794) and is reported to segregate with disease in families. Functional studies show deficient mismatch repair activity, indicating that this variant impacts protein function (Borras E et al., PMID: 23709753; Drost M et al., PMID: 24027009; van der Klift HM et al., PMID: 27435373). This variant resides within the nucleotide binding pocket of the ATPase domain, suggesting an interference with the ATPase function (Borras E et al., PMID: 23709753). Another variant in the same codon, c.137G>A (p.Ser46Asn), has been reported in affected individuals with Lynch syndrome and is considered pathogenic (Everett JN et al., PMID: 25006859; Haraldsdottir S et al., PMID: 26866578, ClinVar Variation ID: 91301). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.03% in Latino/Admixed American population. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PMS2 function. This variant has been reported in the ClinVar database as a pathogenic variant by 20 submitters and likely pathogenic by 16 submitters (ClinVar Variation ID: 9245). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less)
|
|
Likely pathogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090751.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
|
|
Likely pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197212.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
Likely pathogenic
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colon cancer
Affected status: yes
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266116.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
kidney cancer (present) , bladder cancer (present)
Age: 70-79 years
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
endometrial cancer (present)
Age: 40-49 years
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
lymphoma (present) , leukemia (present) , other cancer (present)
Age: 20-29 years
|
|
Pathogenic
(Jan 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Vantari Genetics
Accession: SCV000267076.1
First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016 |
|
|
Pathogenic
(Apr 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV000840051.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
Comment:
This c.137G>T (p.S46I) variant in PMS2 has been reported in individuals with mismatch repair deficiency syndrome, colon, endometrial, colorectal and bladder cancer (PMID: 21376568, 16144131, … (more)
This c.137G>T (p.S46I) variant in PMS2 has been reported in individuals with mismatch repair deficiency syndrome, colon, endometrial, colorectal and bladder cancer (PMID: 21376568, 16144131, 21204794, 22577899, 16619239, 23709753). In addition, functional studies have shown that the c.137G>T (p.S46I) variant significantly impairs mismatch repair activity (PMID: 23709753, 24027009). Therefore, the c.137G>T (p.S46I) in the PMS2 gene is classified as pathogenic. (less)
|
|
Likely pathogenic
(Mar 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Pituitary carcinoma
Affected status: yes
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000853190.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
Comment:
This is a missense variant in which a G is replaced by a T at coding position 137 and is predicted to change a Serine … (more)
This is a missense variant in which a G is replaced by a T at coding position 137 and is predicted to change a Serine to an Isoleucine at codon 46. (less)
Sex: female
|
|
Likely pathogenic
(Feb 27, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227140.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Likely pathogenic
(Sep 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000469744.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
Across a selection of the available literature, the PMS2 c.137G>T (p.Ser46Ile) missense variant has been identified in at least 18 heterozygous or compound heterozygous cases … (more)
Across a selection of the available literature, the PMS2 c.137G>T (p.Ser46Ile) missense variant has been identified in at least 18 heterozygous or compound heterozygous cases with various cancers and three as-yet unaffected heterozygous family members (Agostini et al. 2005; Auclair et al. 2007; Senter et al. 2008; Pastrello et al. 2011; Herkert et al. 2011; Tomsic et al. 2013; Borras et al. 2013). The p.Ser46Ile variant was absent from 188 control individuals and 436 control chromosomes but is reported at a frequency of 0.00022 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant occurs at a strongly conserved residue in an important functional domain. Borras et al. (2013) demonstrated through in vitro expressions studies that the p.Ser46Ile variant had significantly reduced mismatch repair activity, approximately 13% that of wild type, while Drost et al. (2013) showed that the p.Ser46Ile variant had a mismatch repair efficiency similar to that of a known pathogenic variant. Based on the evidence, the p. Ser46Ile variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
Likely pathogenic
(May 01, 2021)
|
criteria provided, single submitter
Method: research
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Laan Lab, Human Genetics Research Group, University of Tartu
Accession: SCV002538616.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Non-obstructive azoospermia (present)
Secondary finding: yes
Method: exome sequencing
|
|
Likely pathogenic
(May 14, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677739.2
First in ClinVar: Jan 20, 2017 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Jul 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004031230.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 |
Comment:
The PMS2 c.137G>T (p.Ser46Ile) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious … (more)
The PMS2 c.137G>T (p.Ser46Ile) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies support that the variant impairs mismatch repair activity (PMID: 23709753). This variant has been observed in several individuals with features consistent with Lynch syndrome and constitutional mismatch repair deficiency, including tumors that have demonstrated microsatellite instability and/or loss of PMS2 by immunohistochemistry (PMID: 17557300, 18273873, 19156169, 19283792, 20205264). In summary, this variant meets criteria to be classified as pathogenic. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
PMS2-related cancer disorders
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046408.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been reported in the heterozygous state in individuals affected with Lynch syndrome-associated cancers (PMID: 15256438, 16619239, 18602922, 23709753, 28596308, 30702970, 31992580) and … (more)
This variant has been reported in the heterozygous state in individuals affected with Lynch syndrome-associated cancers (PMID: 15256438, 16619239, 18602922, 23709753, 28596308, 30702970, 31992580) and in the homozygous or compound heterozygous state in individuals affected with constitutional mismatch repair deficiency syndrome (CMMRD) (PMID: 16144131, 17557300, 21204794, 21376568). In vitro experimental studies have shown that this variant impairs the mismatch repair activity of PMS2 (PMID: 23709753, 24027009). The c.137G>T(p.Ser46Ile) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.017% (48/277180) and is absent in the homozygous state. The c.137G>T(p.Ser46Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.137G>T(p.Ser46Ile) variant is classified as Pathogenic. (less)
|
|
Likely pathogenic
(Jul 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV004183374.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
ACMG classification criteria: PS3, PS4, PM1, PM2, PM3
Geographic origin: Brazil
|
|
Pathogenic
(May 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004223967.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PP5, PM3_strong, PS3
Number of individuals with the variant: 3
|
|
Likely pathogenic
(Sep 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV004228118.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000686122.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with isoleucine at codon 46 in the nucleotide binding pocket of the ATPase domain of the PMS2 protein. Computational prediction … (more)
This missense variant replaces serine with isoleucine at codon 46 in the nucleotide binding pocket of the ATPase domain of the PMS2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant significantly impairs the mismatch repair activity of PMS2 protein (PMID: 23709753, 24027009). This variant has been reported in over 50 individuals affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 15256438, 16619239, 18602922, 23709753, 28596308, 30702970, 31992580) and is thought to be a founder mutation in the Caucasian population (PMID: 22577899, 25345868). This variant has been reported in trans with pathogenic PMS2 variants in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 16144131, 17557300, 21204794, 21376568). This variant has been identified in 48/277180 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253845.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 46 of the PMS2 protein (p.Ser46Ile). … (more)
This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 46 of the PMS2 protein (p.Ser46Ile). This variant is present in population databases (rs121434629, gnomAD 0.03%). This missense change has been observed in individual(s) with constitutional mismatch repair deficiency syndrome (CMMR-D) (PMID: 16144131, 16619239, 21204794, 21376568, 22577899, 23709753). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9245). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 23709753, 24027009). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184825.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.137G>T (p.S46I) alteration is located in coding exon 2 of the PMS2 gene. This alteration results from a G to T substitution at nucleotide … (more)
The c.137G>T (p.S46I) alteration is located in coding exon 2 of the PMS2 gene. This alteration results from a G to T substitution at nucleotide position 137, causing the serine (S) at amino acid position 46 to be replaced by an isoleucine (I). Based on data from gnomAD, the T allele has an overall frequency of 0.017% (48/277180) total alleles studied. The highest observed frequency was 0.031% (11/35326) of Latino alleles. This mutation has been identified in numerous individuals with a tumor exhibiting microsatellite instability and/or loss of PMS2 expression by immunohistochemistry and has been associated with a significant reduction in mismatch repair activity (Clendenning, 2006; Borras, 2013; Drost, 2013; Dudley, 2015). The p.S46I mutation has been reported in a homozygous state or in conjunction with a second PMS2 mutation in multiple individuals with phenotypes consistent with constitutional mismatch repair-deficiency (CMMR-D) (Auclair, 2007; Senter, 2008; Pastrello, 2011; Herkert, 2011; Lavoine, 2015; Rengifo-Cam, 2017). Data supports p.S46I as a founder mutation of likely European origin (Tomsic, 2013). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004205401.3
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Jun 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inherited MMR deficiency (Lynch syndrome)
Affected status: yes
Allele origin:
germline
|
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV005196392.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Comment:
PS4_Very Strong,PM3_Strong,PP3,PP4_Strong
|
|
Pathogenic
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002497503.17
First in ClinVar: Apr 11, 2022 Last updated: Oct 08, 2024 |
Comment:
PMS2: PS3, PS4, PM5
Number of individuals with the variant: 12
|
|
Pathogenic
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Turcot syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190470.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800634.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956600.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001976325.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
Pathogenic
(Aug 01, 2013)
|
no assertion criteria provided
Method: literature only
|
LYNCH SYNDROME 4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV002601716.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Comment on evidence:
Mismatch Repair Cancer Syndrome 4 In 2 sisters with mismatch repair cancer syndrome (MMRCS4; 619101), Auclair et al. (2007) identified compound heterozygosity for 2 mutations … (more)
Mismatch Repair Cancer Syndrome 4 In 2 sisters with mismatch repair cancer syndrome (MMRCS4; 619101), Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the PMS2 gene: a 137G-T transversion in exon 2, resulting in a ser46-to-ile (S46I) substitution, and a frameshift (600259.0011). Lynch Syndrome 4 Borras et al. (2013) identified a heterozygous S46I mutation in 2 members of a Spanish family with hereditary nonpolyposis colorectal cancer-4 (LYNCH4; 614337). One patient had colorectal cancer and the other had 3 skin tumors. An unrelated Spanish patient with bladder cancer also carried the mutation. The substitution is located within the nucleotide binding pocket of the ATPase domain, suggesting an interference with the ATPase function. In vitro functional expression studies showed that the mutant protein had significantly reduced MMR activity (about 13%) compared to controls, confirming its pathogenicity. (less)
|
|
Pathogenic
(Aug 01, 2013)
|
no assertion criteria provided
Method: literature only
|
MISMATCH REPAIR CANCER SYNDROME 4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030047.6
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
Comment on evidence:
Mismatch Repair Cancer Syndrome 4 In 2 sisters with mismatch repair cancer syndrome (MMRCS4; 619101), Auclair et al. (2007) identified compound heterozygosity for 2 mutations … (more)
Mismatch Repair Cancer Syndrome 4 In 2 sisters with mismatch repair cancer syndrome (MMRCS4; 619101), Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the PMS2 gene: a 137G-T transversion in exon 2, resulting in a ser46-to-ile (S46I) substitution, and a frameshift (600259.0011). Lynch Syndrome 4 Borras et al. (2013) identified a heterozygous S46I mutation in 2 members of a Spanish family with hereditary nonpolyposis colorectal cancer-4 (LYNCH4; 614337). One patient had colorectal cancer and the other had 3 skin tumors. An unrelated Spanish patient with bladder cancer also carried the mutation. The substitution is located within the nucleotide binding pocket of the ATPase domain, suggesting an interference with the ATPase function. In vitro functional expression studies showed that the mutant protein had significantly reduced MMR activity (about 13%) compared to controls, confirming its pathogenicity. (less)
|
|
Pathogenic
(Jul 12, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PMS2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004121118.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The PMS2 c.137G>T variant is predicted to result in the amino acid substitution p.Ser46Ile. This variant has been reported as a founder variant in European … (more)
The PMS2 c.137G>T variant is predicted to result in the amino acid substitution p.Ser46Ile. This variant has been reported as a founder variant in European populations (Table 1, Senter et al. 2008. PubMed ID: 18602922; Tomsic et al. 2013. PubMed ID: 22577899; Table 1 and Figure 2, Wang et al. 2020. PubMed ID: 31992580). It has been reported in the heterozygous state in individuals with Lynch syndrome spectrum cancers (Clendenning et al. 2006. PubMed ID: 16619239; Fanale et al. 2022. PubMed ID: 35223509; Table S1, S3, Susswein et al. 2016. PubMed ID: 26681312; Tomsic et al. 2013. PubMed ID: 22577899; Cock-Rada et al. 2018. PubMed ID: 28528518; Brohl et al. 2017. PubMed ID: 28125078; Table S4, Hartman. 2020. PubMed ID: 32782288; Hechtman et al. 2020. PubMed ID: 31857677). This variant has also been reported in the homozygous and compound heterozygous states in individuals with autosomal recessive constitutional mismatch repair-deficiency syndrome (Agostini et al. 2005. PubMed ID: 16144131; Table 1, Herkert et al. 2011. PubMed ID: 21376568). Of note, this variant has also been reported in cis (on the same allele) with a second pathogenic PMS2 variant, c.164–1G>A, in individuals with autosomal dominant Lynch syndrome and is referred to as the c.[137G>T; 164-1G>A] allele (Table 1 and Figure 2, Wang et al. 2020. PubMed ID: 31992580). The c.137G>T (p.Ser46Ile) variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9245/). This variant, in isolation or as the c.[137G>T; 164-1G>A] allele, is interpreted as pathogenic. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Endometrial carcinoma
Affected status: yes
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: SCV000592923.2 First in ClinVar: Dec 06, 2016 Last updated: Apr 13, 2021 |
Comment:
The PMS2 p.Ser46Ile variant was identified in 11 of 1466 proband chromosomes (frequency: 0.008) from individuals or families with hereditary breast and ovarian cancer syndrome … (more)
The PMS2 p.Ser46Ile variant was identified in 11 of 1466 proband chromosomes (frequency: 0.008) from individuals or families with hereditary breast and ovarian cancer syndrome or Lynch syndrome and was not identified in 2490 control chromosomes from healthy individuals (Bodo 2017, Borras 2013, Clendenning 2006, Senter 2008, Pastrello 2011, Dorschner 2013, Nakagawa 2004). The variant was also identified in dbSNP (ID: rs121434629) as “With Pathogenic, Uncertain significance allele”, ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae, and 8 other submitters; and as likely pathogenic by InSiGHT expert panel in 2014 and 7 other submitters), COGR (2x), Insight Colon Cancer Gene Variant Database (1x as class 4), Mismatch Repair Genes Variant Database (4x), and Insight Hereditary Tumors Database (25x). The variant was not identified in Cosmic or Zhejiang Colon Cancer Database. The variant was identified in control databases in 48 of 277180 chromosomes at a frequency of 0.0002 (Genome Aggregation Consortium Feb 27, 2017), in the following populations: Latino in 11 of 35326 chromosomes (frequency: 0.0003) and European in 37 of 125388 chromosomes (frequency: 0.0003); it was not identified in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was identified in several cases with CMRD or Turcot syndrome as a biallelic variant with one of the following PMS2 variants: c.1951C>T, c.2174+1G>A, c.804-2A>G, and c.137G>A (Agostini 2005, Herkert 2011, Giunti 2009, Jackson 2008, Senter 2008). The variant is located within the functional domain of histidine kinase-like ATPase, increasing the likelihood that it may have clinical significance. Functional assays have shown that this variant had reduced mismatch repair efficiency (Drost 2013) and resulted in near absence of the PMS2 protein (Auclair 2007). One study suggests that this variant may by a founder mutation in a population of undetermined ancestry (Tomsic et al 2013). This variant has also been identified by our laboratory in two patients affected with Lynch syndrome and PMS2-deficient colon tumours. The p.Ser46 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that this variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
|
Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918197.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002054088.2
First in ClinVar: Jan 08, 2022 Last updated: Oct 01, 2022 |
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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 |
---|---|---|---|---|
Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features. | Pedroni M | Genes | 2022 | PMID: 36360190 |
Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. | Kasak L | Human reproduction (Oxford, England) | 2022 | PMID: 35535697 |
Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies. | Tlemsani C | Science translational medicine | 2021 | PMID: 33504652 |
Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases. | Quaio CRDC | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 33258288 |
Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
Targeted sequencing of genes associated with the mismatch repair pathway in patients with endometrial cancer. | Singh AK | PloS one | 2020 | PMID: 32634176 |
A Lynch syndrome-associated mutation at a Bergerat ATP-binding fold destabilizes the structure of the DNA mismatch repair endonuclease MutL. | Izuhara K | The Journal of biological chemistry | 2020 | PMID: 32571878 |
Mismatch repair gene pathogenic germline variants in a population-based cohort of breast cancer. | Nguyen-Dumont T | Familial cancer | 2020 | PMID: 32060697 |
CIK cell cytotoxicity is a predictive biomarker for CIK cell immunotherapy in postoperative patients with hepatocellular carcinoma. | Pan QZ | Cancer immunology, immunotherapy : CII | 2020 | PMID: 32060687 |
Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. | Wang Q | Journal of medical genetics | 2020 | PMID: 31992580 |
Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer. | Wu Y | European urology oncology | 2020 | PMID: 31948886 |
Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes. | Hechtman JF | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2020 | PMID: 31857677 |
Constitutional mismatch repair deficiency-associated brain tumors: report from the European C4CMMRD consortium. | Guerrini-Rousseau L | Neuro-oncology advances | 2019 | PMID: 32642664 |
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden. | Okkels H | Genetic testing and molecular biomarkers | 2019 | PMID: 31433215 |
Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process. | Salvador MU | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30702970 |
Cancer susceptibility gene mutations in type I and II endometrial cancer. | Long B | Gynecologic oncology | 2019 | PMID: 30612635 |
Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue. | Shuen AY | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30608896 |
The impact of variant classification on the clinical management of hereditary cancer syndromes. | Turner SA | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29875428 |
No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency. | Tesch VK | Frontiers in immunology | 2018 | PMID: 30013564 |
A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. | Cock-Rada AM | Familial cancer | 2018 | PMID: 28528518 |
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. | Le DT | Science (New York, N.Y.) | 2017 | PMID: 28596308 |
Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome. | Sunga AY | Cancer genetics | 2017 | PMID: 28449805 |
A 30-Year-Old Man with Three Primary Malignancies: A Case of Constitutional Mismatch Repair Deficiency. | Rengifo-Cam W | ACG case reports journal | 2017 | PMID: 28286799 |
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma. | Brohl AS | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28125078 |
Detection of Mismatch Repair Deficiency and Microsatellite Instability in Colorectal Adenocarcinoma by Targeted Next-Generation Sequencing. | Nowak JA | The Journal of molecular diagnostics : JMD | 2017 | PMID: 27863258 |
DNA-Repair Gene Mutations in Metastatic Prostate Cancer. | Foulkes WD | The New England journal of medicine | 2016 | PMID: 27806231 |
Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome. | van der Klift HM | Human mutation | 2016 | PMID: 27435373 |
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. | Pritchard CC | The New England journal of medicine | 2016 | PMID: 27433846 |
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 |
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. | Schrader KA | JAMA oncology | 2016 | PMID: 26556299 |
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. | Lavoine N | Journal of medical genetics | 2015 | PMID: 26318770 |
Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. | Bodo S | Gastroenterology | 2015 | PMID: 26116798 |
Germline MLH1 Mutations Are Frequently Identified in Lynch Syndrome Patients With Colorectal and Endometrial Carcinoma Demonstrating Isolated Loss of PMS2 Immunohistochemical Expression. | Dudley B | The American journal of surgical pathology | 2015 | PMID: 25871621 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. | Ponti G | Clinical genetics | 2015 | PMID: 25345868 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. | Haraldsdottir S | Gastroenterology | 2014 | PMID: 25194673 |
Clinical problem-solving. Spot diagnosis. | Stark Z | The New England journal of medicine | 2014 | PMID: 24897087 |
Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene. | Drost M | Human mutation | 2013 | PMID: 24027009 |
Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. | Borràs E | Journal of medical genetics | 2013 | PMID: 23709753 |
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. | Thompson BA | Human mutation | 2013 | PMID: 22949387 |
Recurrent and founder mutations in the PMS2 gene. | Tomsic J | Clinical genetics | 2013 | PMID: 22577899 |
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 |
Integrated analysis of unclassified variants in mismatch repair genes. | Pastrello C | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21239990 |
Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations. | Leenen CH | Clinical genetics | 2011 | PMID: 21204794 |
The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations. | Durno CA | The American journal of gastroenterology | 2010 | PMID: 20531397 |
Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. | Vaughn CP | Human mutation | 2010 | PMID: 20205264 |
Type A microsatellite instability in pediatric gliomas as an indicator of Turcot syndrome. | Giunti L | European journal of human genetics : EJHG | 2009 | PMID: 19156169 |
The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. | Senter L | Gastroenterology | 2008 | PMID: 18602922 |
Café-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2. | Jackson CC | Pediatric blood & cancer | 2008 | PMID: 18273873 |
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 |
Long-range PCR facilitates the identification of PMS2-specific mutations. | Clendenning M | Human mutation | 2006 | PMID: 16619239 |
Two PMS2 mutations in a Turcot syndrome family with small bowel cancers. | Agostini M | The American journal of gastroenterology | 2005 | PMID: 16144131 |
Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. | Nakagawa H | Cancer research | 2004 | PMID: 15256438 |
Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. | Baker SM | Cell | 1995 | PMID: 7628019 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMS2 | - | - | - | - |
http://www.insight-database.org/classifications/?gene=PMS2&variant=c.137G%3ET | - | - | - | - |
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Text-mined citations for rs121434629 ...
HelpRecord last updated Oct 13, 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.