ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2445+1G>T
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.2445+1G>T
Variation ID: 234604 Accession: VCV000234604.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5977587 (GRCh38) [ NCBI UCSC ] 7: 6017218 (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 Sep 30, 2017 May 12, 2024 Jan 25, 2024 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000007.14:5977586: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
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The frequency of the allele represented by this VCV record.
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PMS2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5155 | 5249 |
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 (6) |
criteria provided, multiple submitters, no conflicts
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Sep 20, 2023 | RCV000219334.31 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV000228982.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 26, 2016 | RCV000507182.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 6, 2021 | RCV000575263.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 4, 2023 | RCV001193818.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 25, 2022 | RCV002494606.3 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001358436.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 25, 2023 | RCV002288907.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 14, 2019 | RCV004017528.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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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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Pathogenic
(Aug 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604887.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Pathogenic
(Aug 05, 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: SCV001470054.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one … (more)
The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. (less)
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Likely pathogenic
(Aug 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581881.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1_STR, PS4_MOD, PS3_SUP, PM2_SUP
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Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Apr 25, 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: SCV002797927.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279559.13
First in ClinVar: May 29, 2016 Last updated: Sep 30, 2023 |
Comment:
Canonical splice site variant demonstrated to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (van der … (more)
Canonical splice site variant demonstrated to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (van der Klift et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20205264, 25525159, 19132747, 27435373, 26110232, 23012243, 25512458, 24362816, 28702897, 26247049, 30787465, 33087929) (less)
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Pathogenic
(Aug 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362952.2
First in ClinVar: Jun 22, 2020 Last updated: Oct 04, 2023 |
Comment:
Variant summary: PMS2 c.2445+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: PMS2 c.2445+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports the variant to result in aberrant transcripts as assessed through minigene assays in HEK293 and HeLa cell lines and also, following analysis of patient RNA where retention of 85bp of flanking intronic sequence was observed (van der Klift_2015). The variant was absent in 194842 control chromosomes. c.2445+1G>T, has been reported in the literature in individuals affected with colorectal cancer (Niessen_2009, Vaughn_2010, ten Broeke_2015) or gynecological cancer (Delahunty_2022). The following publications have been ascertained in the context of this evaluation (PMID: 19132747, 26110232, 20205264, 25512458, 26247049, 35263119). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; seven submitters classified the variant as pathogenic and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Sep 25, 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: SCV004187576.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more)
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
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Pathogenic
(Jul 23, 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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Baylor Genetics
Accession: SCV004207783.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 25, 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: SCV000285122.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 14 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 14 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 19132747, 20205264, 23012243, 25512458, 26110232). ClinVar contains an entry for this variant (Variation ID: 234604). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (PMID: 26247049; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Trp841Glyfs*10) have been determined to be pathogenic (PMID: 10037723, 16338176, 20533529, 26116798, 28218421). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely Pathogenic
(Oct 14, 2019)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848307.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.2445+1G>T variant in PMS2 has been reported in at least 3 individuals suspected to have Lynch syndrome (Vaughn 2010, Niessen 2009, ten Broeke 2015). … (more)
The c.2445+1G>T variant in PMS2 has been reported in at least 3 individuals suspected to have Lynch syndrome (Vaughn 2010, Niessen 2009, ten Broeke 2015). It was absent from large population studies and was classified as Pathogenic by several clinical labs (Variation ID 234604). This variant occurs within the canonical splice site (+/- 1,2) (within last intron) and is predicted to cause altered splicing leading to an abnormal or absent protein. Minigene assays and patient RNA studies demonstrate an impact on splicing (van der Klift 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM2, PS4_Supporting, PVS1_Strong, PS3_Moderate. (less)
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Pathogenic
(Oct 06, 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: SCV000670739.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.2445+1G>T pathogenic mutation results from a G to T substitution one nucleotide after coding exon 14 of the PMS2 gene. This alteration has been … (more)
The c.2445+1G>T pathogenic mutation results from a G to T substitution one nucleotide after coding exon 14 of the PMS2 gene. This alteration has been reported in two HNPCC/Lynch syndrome patients: one with an MSI-H colorectal cancer diagnosed at 31 years of age and the other with a transverse colon cancer diagnosed at age 34 which demonstrated isolated absence of PMS2 on immunohistochemistry (IHC) (Niessen R et al. Genes Chromosomes Cancer. 2009 Apr;48(4):322-9; Vaughn C et al. Hum. Mutat. 2010 May;31(5):588-93). RNA studies for c.2445+1G>T demonstrated the presence of an aberrant transcript leading to premature protein truncation; however, levels of full-length/normal transcript were not assessed (van der Klift H et al. Mol. Genet. Genomic Med. 2015 Jul;3(4):327-45). This position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(May 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247255.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000691958.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554166.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PMS2 c.2445+1G>T variant was identified in 3 of 1152 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome or colorectal cancer (Niessen … (more)
The PMS2 c.2445+1G>T variant was identified in 3 of 1152 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome or colorectal cancer (Niessen 2009, Suerink 2015, ten Broeke 2015). The variant was also identified in dbSNP (ID: rs876661113) as "With Likely pathogenic, Pathogenic allele" and ClinVar (classified as pathogenic by Invitae, ARUP, Ambry Genetics and GeneDx). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.2445+1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. Further, RNA-based mutation scanning found this variant produced two aberrant splice products in cultured lymphocyte RNA (van der Klift 2015). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(-)
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742120.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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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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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: SCV001952646.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members. | Delahunty R | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2022 | PMID: 35263119 |
Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome. | Maletzki C | Molecular carcinogenesis | 2017 | PMID: 28218421 |
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 |
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 |
Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. | Bodo S | Gastroenterology | 2015 | PMID: 26116798 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. | ten Broeke SW | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25512458 |
The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. | Vaughn CP | Genes, chromosomes & cancer | 2013 | PMID: 23012243 |
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 |
Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair. | Kosinski J | Human mutation | 2010 | PMID: 20533529 |
Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. | Vaughn CP | Human mutation | 2010 | PMID: 20205264 |
PMS2 involvement in patients suspected of Lynch syndrome. | Niessen RC | Genes, chromosomes & cancer | 2009 | PMID: 19132747 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Truncation of the C-terminus of human MLH1 blocks intracellular stabilization of PMS2 and disrupts DNA mismatch repair. | Mohd AB | DNA repair | 2006 | PMID: 16338176 |
The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. | Guerrette S | The Journal of biological chemistry | 1999 | PMID: 10037723 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs876661113 ...
HelpRecord last updated May 12, 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.