ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.94G>T (p.Val32Leu)
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.
Uncertain significance(3); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.94G>T (p.Val32Leu)
Variation ID: 411049 Accession: VCV000411049.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 6005961 (GRCh38) [ NCBI UCSC ] 7: 6045592 (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 29, 2017 Feb 20, 2024 Jan 24, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.94G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Val32Leu missense NM_001322003.2:c.-312G>T 5 prime UTR NM_001322004.2:c.-242-1903G>T intron variant NM_001322005.2:c.-312G>T 5 prime UTR NM_001322006.2:c.94G>T NP_001308935.1:p.Val32Leu missense NM_001322007.2:c.-122G>T 5 prime UTR NM_001322008.2:c.-52-1903G>T intron variant NM_001322009.2:c.-312G>T 5 prime UTR NM_001322010.2:c.-242-1903G>T intron variant NM_001322011.2:c.-791G>T 5 prime UTR NM_001322012.2:c.-791G>T 5 prime UTR NM_001322013.2:c.-312G>T 5 prime UTR NM_001322014.2:c.94G>T NP_001308943.1:p.Val32Leu missense NM_001322015.2:c.-391G>T 5 prime UTR NR_136154.1:n.181G>T non-coding transcript variant NC_000007.14:g.6005961C>A NC_000007.13:g.6045592C>A NG_008466.1:g.8146G>T NG_050738.1:g.1711C>A LRG_161:g.8146G>T LRG_161t1:c.94G>T - Protein change
- V32L
- Other names
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- Canonical SPDI
- NC_000007.14:6005960:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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 |
5052 | 5152 |
Conditions - Germline
Condition
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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
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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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Likely benign (1) |
criteria provided, single submitter
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Jan 24, 2024 | RCV000473006.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 13, 2023 | RCV000562693.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 1, 2018 | RCV000485503.2 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001356469.1 |
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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Uncertain significance
(Jun 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568131.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted PMS2 c.94G>T at the cDNA level, p.Val32Leu (V32L) at the protein level, and results in the change of a Valine to … (more)
This variant is denoted PMS2 c.94G>T at the cDNA level, p.Val32Leu (V32L) at the protein level, and results in the change of a Valine to a Leucine (GTA>TTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Val32Leu was not observed in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Val32Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Oct 21, 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: SCV000670788.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.V32L variant (also known as c.94G>T), located in coding exon 2 of the PMS2 gene, results from a G to T substitution at nucleotide … (more)
The p.V32L variant (also known as c.94G>T), located in coding exon 2 of the PMS2 gene, results from a G to T substitution at nucleotide position 94. The valine at codon 32 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Nov 13, 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: SCV000686259.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with leucine at codon 32 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces valine with leucine at codon 32 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jan 24, 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: SCV000551997.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(-)
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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: SCV001551646.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PMS2 p.Val32Leu variant was not identified in the literature. The variant was identified in dbSNP (ID: rs977251189) as "With Uncertain significance allele", and in … (more)
The PMS2 p.Val32Leu variant was not identified in the literature. The variant was identified in dbSNP (ID: rs977251189) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, and Color). The variant was not identified in the following databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Val32 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs977251189 ...
HelpRecord last updated Feb 28, 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.