ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.825A>G (p.Gln275=)
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.825A>G (p.Gln275=)
Variation ID: 232390 Accession: VCV000232390.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5995612 (GRCh38) [ NCBI UCSC ] 7: 6035243 (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 19, 2017 Jul 7, 2024 Mar 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.825A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Gln275= synonymous NM_001322003.2:c.420A>G NP_001308932.1:p.Gln140= synonymous NM_001322004.2:c.420A>G NP_001308933.1:p.Gln140= synonymous NM_001322005.2:c.420A>G NP_001308934.1:p.Gln140= synonymous NM_001322006.2:c.825A>G NP_001308935.1:p.Gln275= synonymous NM_001322007.2:c.507A>G NP_001308936.1:p.Gln169= synonymous NM_001322008.2:c.507A>G NP_001308937.1:p.Gln169= synonymous NM_001322009.2:c.420A>G NP_001308938.1:p.Gln140= synonymous NM_001322010.2:c.420A>G NP_001308939.1:p.Gln140= synonymous NM_001322011.2:c.-109A>G 5 prime UTR NM_001322012.2:c.-109A>G 5 prime UTR NM_001322013.2:c.252A>G NP_001308942.1:p.Gln84= synonymous NM_001322014.2:c.825A>G NP_001308943.1:p.Gln275= synonymous NM_001322015.2:c.516A>G NP_001308944.1:p.Gln172= synonymous NR_136154.1:n.912A>G non-coding transcript variant NC_000007.14:g.5995612T>C NC_000007.13:g.6035243T>C NG_008466.1:g.18495A>G LRG_161:g.18495A>G LRG_161t1:c.825A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000007.14:5995611: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5232 | 5334 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 26, 2023 | RCV000219153.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 19, 2022 | RCV000479060.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763588.3 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 5, 2024 | RCV001267893.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 21, 2023 | RCV000541550.9 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003165571.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 4, 2024 | RCV004525906.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 18, 2023 | RCV003997969.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Mismatch repair cancer syndrome 1
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894427.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Likely pathogenic
(Sep 19, 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: SCV000568206.7
First in ClinVar: Apr 27, 2017 Last updated: Apr 15, 2023 |
Comment:
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Goodenberger et al., 2016; Suerink et al., 2016; Zhang … (more)
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Goodenberger et al., 2016; Suerink et al., 2016; Zhang et al., 2022); Published functional studies demonstrate use of cryptic downstream splice acceptor site resulting in loss of 22 bases and a prematurely truncated transcript (Johannesma et al., 2011; van der Klift et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30256826, 27435373, 21261604, 26247049, 25856668, 28514183, 30787465, 26110232, 30589920, 35477782, 34172528) (less)
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Pathogenic
(Sep 21, 2023)
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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: SCV000625697.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects codon 275 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 275 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individual(s) with Lynch syndrome and symptoms consistent with constitutional mismatch repair deficiency (CMMR-D) (PMID: 21261604, 25856668, 26110232, 28514183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 232390). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 28, 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: SCV000276519.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.825A>G pathogenic mutation (also known as p.Q275Q), located in coding exon 8, results from an A to G substitution at nucleotide position 825 of … (more)
The c.825A>G pathogenic mutation (also known as p.Q275Q), located in coding exon 8, results from an A to G substitution at nucleotide position 825 of the PMS2 gene. This nucleotide substitution does not change the amino acid at codon 275. In one study, this alteration was detected in trans with a pathogenic PMS2 mutation in a patient diagnosed with rectal adenomatous polyps, cutaneous lentigines, and hyperpigmentation at age 24 whose family history included a sister with a brain tumor at age 11; these findings are consistent with constitutional mismatch repair deficiency (CMMR-D). RNA analysis of this variant showed abnormal splicing leading to premature protein truncation, and absence of PMS2 by immunohistochemistry was noted in the adenoma, brain tumor, and normal tissues from the proband and the affected sister (Johannesma PC et al. Clin. Genet. 2011 Sep;80:243-55). Additionally, a minigene assay of this variant showed out of frame skipping of the first 22 nucleotides of exon 8, and no full length transcript was produced from the variant allele (van der Klift HM et al. Mol Genet Genomic Med 2015 Jul;3:327-45). This alteration was also reported in conjunction with an alteration in MLH1 (p.Y684D) in a patient diagnosed with colon at 35 years old, belonged to an Amsterdam I family, and showed absent staining of MLH1/PMS2 on IHC (Martin-Morales L et al. PLoS ONE, 2018 Sep;13:e0203885). Of note, this alteration has also been reported in a patient with breast cancer diagnosed at age 52 (Goodenberger ML et al. Genet. Med. 2016 Jan;18:13-9). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: research
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Lynch syndrome 4
Affected status: no
Allele origin:
germline
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV002762835.2
First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023 |
Comment:
PS3, PS4_SUP, PM2_SUP
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Likely pathogenic
(Sep 19, 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: SCV004187563.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].
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Pathogenic
(Jun 26, 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: SCV004359653.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a … (more)
This synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a de novo splice acceptor site 22 nucleotides downstream of the native intron 7/exon 8 splice acceptor site. RNA studies in patient cells (PMID: 21261604) and by minigene analysis (PMID: 26247049) have shown that this variant results in use of the de novo acceptor site in exon 8, resulting in a 22 nucleotide deletion in the mRNA, causing a frameshift and protein truncation. Absence of PMS2 in patient cells by immunohistochemistry has been observed. (PMID: 21261604). This variant has been reported in individuals with phenotypes consistent with constitutional mismatch repair deficiency (CMMRD; PMID: 21261604). This variant has been identified in 2/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Sep 18, 2023)
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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: SCV004839907.1
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 synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a … (more)
This synonymous variant causes a A>G nucleotide change in exon 8 of the PMS2 gene. Splice site prediction tools indicate that this variant creates a de novo splice acceptor site 22 nucleotides downstream of the native intron 7/exon 8 splice acceptor site. RNA studies in patient cells (PMID: 21261604) and by minigene analysis (PMID: 26247049) have shown that this variant results in use of the de novo acceptor site in exon 8, resulting in a 22 nucleotide deletion in the mRNA, causing a frameshift and protein truncation. Absence of PMS2 in patient cells by immunohistochemistry has been observed. (PMID: 21261604). This variant has been reported in individuals with phenotypes consistent with constitutional mismatch repair deficiency (CMMRD; PMID: 21261604). This variant has been identified in 2/251422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 05, 2024)
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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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Baylor Genetics
Accession: SCV004183532.2
First in ClinVar: Dec 24, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Mar 04, 2024)
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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: SCV005040410.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: PMS2 c.825A>G alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict a significant impact on normal splicing: Three predict the … (more)
Variant summary: PMS2 c.825A>G alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 3' acceptor site. Publications report experimental evidence that this variant affects mRNA splicing, resulting in a deletion of 22 nt (Johannesma_2011, van der Klift_2015). The variant allele was found at a frequency of 8e-06 in 251422 control chromosomes (gnomAD). c.825A>G has been reported in the literature in the compound heterozygous state with other pathogenic variants in individuals affected with features of constitutional mismatch repair deficiency (e.g. Johannesma_2011, Mishra_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21261604, 26247049, 35532657). ClinVar contains an entry for this variant (Variation ID: 232390). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Oct 10, 2019)
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no assertion criteria provided
Method: clinical testing
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Hereditary nonpolyposis colorectal cancer type 4
Affected status: no
Allele origin:
unknown
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV001446383.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020
Comment:
PMS2 (p.Q275Q, NM 000535.5:c.825A>G) is a synonymous variant that is predicted to create a cryptic splice acceptor site. Experimental splice studies have shown that this … (more)
PMS2 (p.Q275Q, NM 000535.5:c.825A>G) is a synonymous variant that is predicted to create a cryptic splice acceptor site. Experimental splice studies have shown that this variant causes aberrant splicing (PMID: 27435373) and leads to loss of function of the PMS2 protein. This variant has been seen to co-occur with another likely pathogenic variant in PMS2 in an individual with constitutional mismatch repair deficiency (CMMRD) (internal laboratory data). This evidence is consistent with a likely pathogenic classification. (less)
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Genotyping Development, RIKEN
Accession: SCV002758050.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 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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Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
Germline Biallelic Mismatch Repair Deficiency in Childhood Glioblastoma and Implications for Clinical Management. | Mishra AK | Neurology India | 2022 | PMID: 35532657 |
Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition. | Martin-Morales L | PloS one | 2018 | PMID: 30256826 |
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers. | Suerink M | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26110232 |
PMS2 monoallelic mutation carriers: the known unknown. | Goodenberger ML | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 25856668 |
Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses. | van der Klift HM | Molecular genetics & genomic medicine | 2015 | PMID: 26247049 |
Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations. | Johannesma PC | Clinical genetics | 2011 | PMID: 21261604 |
Text-mined citations for rs876659736 ...
HelpRecord last updated Jul 15, 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.