This variant is denoted PMS2 c.163+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the PMS2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on currently available evidence, we consider PMS2 c.163+1G>A to be a likely pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.163+1G>A
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.163+1G>A
Variation ID: 422321 Accession: VCV000422321.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 6005891 (GRCh38) [ NCBI UCSC ] 7: 6045522 (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 Apr 27, 2017 May 1, 2024 Sep 18, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
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- Other names
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- Canonical SPDI
- NC_000007.14:6005890:C:T
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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.
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- Links
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 |
5241 | 5343 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 26, 2022 | RCV000481277.5 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2022 | RCV000569035.7 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Sep 18, 2023 | RCV003449226.1 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Oct 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000571765.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted PMS2 c.163+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the PMS2 … (more)
This variant is denoted PMS2 c.163+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the PMS2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on currently available evidence, we consider PMS2 c.163+1G>A to be a likely pathogenic variant. (less)
|
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Likely pathogenic
(Oct 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001350139.2
First in ClinVar: Mar 25, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant causes a G>A nucleotide substitution at the +1 position of intron 2 of the PMS2 gene. Splice site prediction tools predict that this … (more)
This variant causes a G>A nucleotide substitution at the +1 position of intron 2 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
|
|
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Likely pathogenic
(Oct 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888397.4
First in ClinVar: Apr 27, 2017 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts a canonical splice-donor site and is predicted to interfere with normal PMS2 mRNA splicing. This variant has not been reported in large, … (more)
This variant disrupts a canonical splice-donor site and is predicted to interfere with normal PMS2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 28888541 (2017)). Based on the available information, this variant is classified as likely pathogenic. (less)
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000670798.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.163+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the PMS2 gene. This variant has … (more)
The c.163+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the PMS2 gene. This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated loss of PMS2 expression by immunohistochemistry and/or high microsatellite instability (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Sep 18, 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
|
Myriad Genetics, Inc.
Accession: SCV004187648.1
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)
|
Comment:
Comment:
This variant causes a G>A nucleotide substitution at the +1 position of intron 2 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
This variant disrupts a canonical splice-donor site and is predicted to interfere with normal PMS2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 28888541 (2017)). Based on the available information, this variant is classified as likely pathogenic.
Comment:
The c.163+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the PMS2 gene. This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated loss of PMS2 expression by immunohistochemistry and/or high microsatellite instability (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
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. |
Comment:
This variant is denoted PMS2 c.163+1G>A or IVS2+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 2 of the PMS2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on currently available evidence, we consider PMS2 c.163+1G>A to be a likely pathogenic variant.
Comment:
This variant causes a G>A nucleotide substitution at the +1 position of intron 2 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
This variant disrupts a canonical splice-donor site and is predicted to interfere with normal PMS2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 28888541 (2017)). Based on the available information, this variant is classified as likely pathogenic.
Comment:
The c.163+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the PMS2 gene. This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated loss of PMS2 expression by immunohistochemistry and/or high microsatellite instability (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. | Lilyquist J | Gynecologic oncology | 2017 | PMID: 28888541 |
Text-mined citations for rs1064795705 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.