ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.1A>G (p.Met1Val)
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.1A>G (p.Met1Val)
Variation ID: 91323 Accession: VCV000091323.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 6009019 (GRCh38) [ NCBI UCSC ] 7: 6048650 (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 19, 2014 May 1, 2024 Jun 30, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.1A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Met1Val missense initiator codon variant NM_001322003.2:c.-400A>G 5 prime UTR NM_001322004.2:c.-265A>G 5 prime UTR NM_001322005.2:c.-595A>G 5 prime UTR NM_001322006.2:c.1A>G NP_001308935.1:p.Met1Val missense initiator codon variant NM_001322007.2:c.-215A>G 5 prime UTR NM_001322008.2:c.-75A>G 5 prime UTR NM_001322009.2:c.-590A>G 5 prime UTR NM_001322010.2:c.-265A>G 5 prime UTR NM_001322011.2:c.-884A>G 5 prime UTR NM_001322012.2:c.-879A>G 5 prime UTR NM_001322013.2:c.-400A>G 5 prime UTR NM_001322014.2:c.1A>G NP_001308943.1:p.Met1Val missense initiator codon variant NM_001322015.2:c.-479A>G 5 prime UTR NR_136154.1:n.88A>G non-coding transcript variant NC_000007.14:g.6009019T>C NC_000007.13:g.6048650T>C NG_008466.1:g.5088A>G NG_050738.1:g.4769T>C LRG_161:g.5088A>G LRG_161t1:c.1A>G - Protein change
- M1V
- Other names
- p.M1V:ATG>GTG
- Canonical SPDI
- NC_000007.14:6009018:T:C
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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) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
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
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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 |
5155 | 5249 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Mar 20, 2024 | RCV000076838.14 | |
Likely pathogenic (3) |
reviewed by expert panel
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Jun 30, 2017 | RCV000144649.5 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV000160894.21 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 5, 2023 | RCV000410400.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2023 | RCV000564071.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 17, 2024 | RCV000524456.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 18, 2020 | RCV001293980.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 25, 2020 | RCV001280543.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 15, 2020 | RCV001523838.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2024 | RCV003982873.1 |
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
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 30, 2017)
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reviewed by expert panel
Method: curation
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000108326.4
First in ClinVar: Dec 19, 2013 Last updated: Sep 03, 2023 |
Comment:
meets criteria for Class 4
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Likely pathogenic
(Mar 08, 2016)
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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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Counsyl
Accession: SCV000488365.3
First in ClinVar: Jan 09, 2017 Last updated: Sep 03, 2023 |
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Pathogenic
(Jul 28, 2022)
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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: SCV000211586.18
First in ClinVar: Feb 24, 2015 Last updated: Sep 03, 2023 |
Comment:
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Observed in patients in the heterozygous state with Lynch-related cancers … (more)
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Observed in patients in the heterozygous state with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Borras et al., 2013; Okkels et al., 2019; Tian et al., 2019; Wang et al., 2020); This variant is associated with the following publications: (PMID: 19283792, 25512458, 22577899, 32068069, 28466842, 31433215, 31447099, 21376568, 23709753, 20487569, 23012243, 21261604, 27064304, 28514183, 27476653, 26895986, 27435373, 26681312, 29485237, 28491141, 25980754, 31054147, 31491536, 31992580, 34308366, 30787465, 33087929, 18602922) (less)
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Pathogenic
(Nov 23, 2022)
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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: SCV000601834.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The frequency of this variant … (more)
This variant disrupts the translation initiation codon of the PMS2 mRNA and is predicted to interfere with PMS2 protein synthesis. The frequency of this variant in the general population, 0.000023 (3/128208 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMID: 20487569 (2010)), endometrial cancer (PMID: 23709753 (2013)), and constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 18602922 (2008)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000166382.14
First in ClinVar: Jun 23, 2014 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects the initiator methionine of the PMS2 mRNA. The next in-frame methionine is located at codon 136. This variant is present in … (more)
This sequence change affects the initiator methionine of the PMS2 mRNA. The next in-frame methionine is located at codon 136. This variant is present in population databases (rs587779333, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with colorectal cancer, endometrial cancer, and/or individuals with a personal history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20487569, 23709753; Invitae). ClinVar contains an entry for this variant (Variation ID: 91323). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 26, 2021)
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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: SCV000663423.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the PMS2 gene and results from an A to G … (more)
The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the PMS2 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This mutation has been previously identified in 3 probands with early-onset, Lynch syndrome-associated malignancies and tumors demonstrating isolated loss of PMS2 staining by immunohistochemistry (IHC). Of note, all 3 probands were determined to carry the c.1A>G (p.M1?) mutation in conjunction with a pathogenic PMS2 mutation in trans and had a clinically distinct (more severe) phenotype compared to monoallelic PMS2 mutation carriers (Senter et al. Gastroenterology. 2008 Aug;135(2):419-28). This alteration has been reported in individuals with biallelic PMS2 mutations and phenotypes consistent with constitutional mismatch repair deficiency (CMMRD) (Johannesma PC et al. Clin Genet. 2011 Sep;80(3):243-55; Ambry internal data). In other studies, this mutation has been identified in multiple patients with Lynch syndrome, including those whose tumors have demonstrated isolated loss of PMS2 by IHC and/or microsatellite instability (Borràs E et al. J. Med. Genet. 2013 Aug; 50(8):552-63; Cadoo KA et al. JCO Precis Oncol. 2019 Apr;3; Wang Q et al. J Med Genet. 2020 07;57(7):487-99). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Oct 20, 2017)
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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: SCV000885991.2
First in ClinVar: Feb 17, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: no
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001439942.2
First in ClinVar: Oct 31, 2020 Last updated: Sep 03, 2023 |
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Pathogenic
(Dec 25, 2020)
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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: SCV000697323.3
First in ClinVar: Dec 26, 2017 Last updated: Sep 03, 2023 |
Comment:
Variant summary: PMS2 c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: PMS2 c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250382 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (5.6e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.1A>G has been reported in the literature in individuals affected with LS but also in unaffected individuals, or in patients with co-occurring pathogenic PMS2 variants (Borras_2013, Senter_2008, Sjursen_2016). In three of these biallelic PMS2 patients the phenotype was more suggestive of constitutional mismatch repair deficiency syndrome (CMMRD) than LS, moreover IHC results demonstrated loss of PMS2 expression in the tumors as well as in the adjacent unaffected tissues. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories and one expert panel (InSight) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic, some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 15, 2020)
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criteria provided, single submitter
Method: research
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Mismatch repair cancer syndrome 4
Affected status: no
Allele origin:
germline
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Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478145.2
First in ClinVar: Jun 19, 2021 Last updated: Sep 03, 2023 |
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Pathogenic
(Nov 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mismatch repair cancer syndrome 1
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482720.2 First in ClinVar: Mar 07, 2021 Last updated: Sep 03, 2023 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple patients [PMID 18602922, 23709753, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in multiple patients [PMID 18602922, 23709753, 28491141, 26681312] (less)
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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: SCV004019881.2
First in ClinVar: Jul 29, 2023 Last updated: Sep 03, 2023 |
Comment:
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. … (more)
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30680046, 27476653, 18602922]. (less)
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Pathogenic
(Nov 04, 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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Revvity Omics, Revvity
Accession: SCV002018876.4
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Feb 06, 2024)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760391.4
First in ClinVar: Dec 17, 2022 Last updated: Feb 14, 2024 |
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Pathogenic
(Feb 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000691053.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant results in the loss of the translation initiator methionine at codon 1 of the PMS2 protein. Next in-frame methionine occurs at codon 136 … (more)
This variant results in the loss of the translation initiator methionine at codon 1 of the PMS2 protein. Next in-frame methionine occurs at codon 136 in exon 4. Exons 1 through 10 of the PMS2 gene encodes a functionally important ATPase domain. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (PMID: 20487569, 23012243, 23709753, 27064304, 31992580, 32775946). This variant has been observed in trans with pathogenic variants in three unrelated individuals with personal cancer history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). There was no detectable PMS2 protein expression in these individuals. This variant has been identified in 8/281624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different nucleotide substitutions impacting methionine at codon 1 (c.1A>T, c.1A>C, c.2T>C, c.2T>A, c.2T>G, c.3G>A, c.3G>C) are known to be disease-causing (ClinVar variation ID: 142777, 820477, 127788, 182809, 231873, 450786, 957082). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Mar 20, 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: SCV000711436.5
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The p.Met1? (c.1A>G) variant in PMS2 has been reported in the heterozygous state in at least 8 individuals with Lynch syndrome-associated cancers and 4 individuals … (more)
The p.Met1? (c.1A>G) variant in PMS2 has been reported in the heterozygous state in at least 8 individuals with Lynch syndrome-associated cancers and 4 individuals who were referred for clinical genetic testing of germline cancer genes (Talseth-Palmer 2010 PMID: 20487569, Borras 2013 PMID: 23709753, Vaughn 2013 PMID: 23012243, Susswein 2016 PMID: 26681312, Brennan 2017 PMID: 28491141, Tian 2019 PMID: 31054147, Yanus 2020 PMID: 31491536, Wang 2020 PMID: 31992580, Kwong 2020 PMID: 32068069, Singh 2023 PMID: 37296477), including at least one individual with tumour analysis showing loss of PMS2 by immunohistochemistry (IHC). It has also been also reported in the compound heterozygous state in at least 3 individuals with features of constitutional mismatch repair deficiency (CMMRD; Senter 2008 PMID: 18602922, LOVD database) with tumors demonstrating loss of PMS2 expression by IHC. It has also been identified in 0.003% (33/1179848) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This variant affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation although a variety of outcomes (no protein synthesis or the activation of an alternative translation initiation codon) are possible. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch Syndrome. Moreover, this variant has been classified as Likely Pathogenic on June 30, 2017 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108326.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PS4_Moderate, PM3_Strong, PM2_Supporting. (less)
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Likely pathogenic
(Jan 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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PMS2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004797622.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The PMS2 c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported along with a second PMS2 pathogenic … (more)
The PMS2 c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported along with a second PMS2 pathogenic variant in individuals with early onset (<30 years) colorectal cancer (Senter et al. 2008. PubMed ID: 18602922, Table 3) and has been reported alone, in the heterozygous state, in many individuals with personal and/or family histories of Lynch syndrome cancers (Borràs et al. 2013. PubMed ID: 23709753, Table 1; Brennan et al. 2017. PubMed ID: 28491141, Table 6; Tian et al. 2019. PubMed ID: 31054147, Table S1, Patient EC132; Wang et al. 2020. PubMed ID: 31992580, Table 1). It has also been reported in individuals with breast cancer (Susswein et al. 2015. PubMed ID: 26681312, Table S1; Wang et al. 2020. PubMed ID: 31992580, Table 1). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91323/). Furthermore, multiple variants in PMS2 that result in a start loss have been associated with PMS2-related cancers and are interpreted as likely pathogenic or pathogenic in ClinVar (Human Gene Mutation Database; ClinVar Variation IDs: 142777, 820477, 182809, 127788, 450786). The c.1A>G variant is interpreted as likely pathogenic. (less)
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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: SCV004842189.1
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:
This variant results in the loss of the translation initiator methionine at codon 1 of the PMS2 protein. Next in-frame methionine occurs at codon 136 … (more)
This variant results in the loss of the translation initiator methionine at codon 1 of the PMS2 protein. Next in-frame methionine occurs at codon 136 in exon 4. Exons 1 through 10 of the PMS2 gene encodes a functionally important ATPase domain. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (PMID: 20487569, 23012243, 23709753, 27064304, 31992580, 32775946). This variant has been observed in trans with pathogenic variants in three unrelated individuals with personal cancer history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). There was no detectable PMS2 protein expression in these individuals. This variant has been identified in 8/281624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different nucleotide substitutions impacting methionine at codon 1 (c.1A>T, c.1A>C, c.2T>C, c.2T>A, c.2T>G, c.3G>A, c.3G>C) are known to be disease-causing (ClinVar variation ID: 142777, 820477, 127788, 182809, 231873, 450786, 957082). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 3
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Likely pathogenic
(Jul 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome I
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000189976.2
First in ClinVar: Oct 19, 2014 Last updated: Sep 03, 2023 |
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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: SCV002054089.3
First in ClinVar: Jan 08, 2022 Last updated: Sep 03, 2023 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing. | Singh AK | BMC medical genomics | 2023 | PMID: 37296477 |
Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
Germline Mutation in 1338 BRCA-Negative Chinese Hereditary Breast and/or Ovarian Cancer Patients: Clinical Testing with a Multigene Test Panel. | Kwong A | The Journal of molecular diagnostics : JMD | 2020 | PMID: 32068069 |
Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. | Wang Q | Journal of medical genetics | 2020 | PMID: 31992580 |
The spectrum of Lynch syndrome-associated germ-line mutations in Russia. | Yanus GA | European journal of medical genetics | 2020 | PMID: 31491536 |
Understanding inherited risk in unselected newly diagnosed patients with endometrial cancer. | Cadoo KA | JCO precision oncology | 2019 | PMID: 32775946 |
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 |
Screening for hereditary cancers in patients with endometrial cancer reveals a high frequency of germline mutations in cancer predisposition genes. | Tian W | International journal of cancer | 2019 | PMID: 31054147 |
Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes. | Henn J | Hereditary cancer in clinical practice | 2019 | PMID: 30680046 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Universal molecular screening does not effectively detect Lynch syndrome in clinical practice. | Brennan B | Therapeutic advances in gastroenterology | 2017 | PMID: 28491141 |
Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. | Adam R | American journal of human genetics | 2016 | PMID: 27476653 |
Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations. | Sjursen W | Molecular genetics & genomic medicine | 2016 | PMID: 27064304 |
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 |
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 |
The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. | Vaughn CP | Genes, chromosomes & cancer | 2013 | PMID: 23012243 |
Recurrent and founder mutations in the PMS2 gene. | Tomsic J | Clinical genetics | 2013 | PMID: 22577899 |
Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations. | Johannesma PC | Clinical genetics | 2011 | PMID: 21261604 |
MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. | Talseth-Palmer BA | Hereditary cancer in clinical practice | 2010 | PMID: 20487569 |
The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. | Senter L | Gastroenterology | 2008 | PMID: 18602922 |
http://www.insight-database.org/classifications/?gene=PMS2&variant=c.1A%3EG | - | - | - | - |
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Text-mined citations for rs587779333 ...
HelpRecord last updated May 08, 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.