ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.89A>G (p.Gln30Arg)
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(9); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000535.7(PMS2):c.89A>G (p.Gln30Arg)
Variation ID: 185474 Accession: VCV000185474.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p22.1 7: 6005966 (GRCh38) [ NCBI UCSC ] 7: 6045597 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 6, 2017 May 1, 2024 Nov 20, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000535.7:c.89A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Gln30Arg missense NM_001322003.2:c.-317A>G 5 prime UTR NM_001322004.2:c.-242-1908A>G intron variant NM_001322005.2:c.-317A>G 5 prime UTR NM_001322006.2:c.89A>G NP_001308935.1:p.Gln30Arg missense NM_001322007.2:c.-127A>G 5 prime UTR NM_001322008.2:c.-52-1908A>G intron variant NM_001322009.2:c.-317A>G 5 prime UTR NM_001322010.2:c.-242-1908A>G intron variant NM_001322011.2:c.-796A>G 5 prime UTR NM_001322012.2:c.-796A>G 5 prime UTR NM_001322013.2:c.-317A>G 5 prime UTR NM_001322014.2:c.89A>G NP_001308943.1:p.Gln30Arg missense NM_001322015.2:c.-396A>G 5 prime UTR NR_136154.1:n.176A>G non-coding transcript variant NC_000007.14:g.6005966T>C NC_000007.13:g.6045597T>C NG_008466.1:g.8141A>G NG_050738.1:g.1716T>C LRG_161:g.8141A>G LRG_161t1:c.89A>G - Protein change
- Q30R
- Other names
- -
- Canonical SPDI
- NC_000007.14:6005965:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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 | ||
---|---|---|---|---|---|---|
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. |
|||
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Oct 26, 2023 | RCV000164904.12 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 14, 2023 | RCV000198290.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 18, 2023 | RCV000410641.4 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 27, 2022 | RCV000482199.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002247569.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Nov 20, 2023 | RCV003995377.2 |
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
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Apr 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207859.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Likely benign
(Mar 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215592.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
Uncertain significance
(Oct 10, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000571957.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
This variant is denoted PMS2 c.89A>G at the cDNA level, p.Gln30Arg (Q30R) at the protein level, and results in the change of a Glutamine to … (more)
This variant is denoted PMS2 c.89A>G at the cDNA level, p.Gln30Arg (Q30R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Gln30Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Gln30Arg occurs at a position that is conserved across species and is located within the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Gln30Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
|
|
Uncertain significance
(Oct 26, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489607.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
Uncertain significance
(Jul 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219031.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.0000041 (1/245770 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer … (more)
The frequency of this variant in the general population, 0.0000041 (1/245770 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in 8 individuals with breast cancer as well as in 2 healthy controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
Uncertain significance
(Oct 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000909683.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamine with arginine at codon 30 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces glutamine with arginine at codon 30 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been identified in 1/245770 chromosomes 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)
|
|
Uncertain significance
(Aug 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000254619.9
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 185474). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (rs56203955, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 30 of the PMS2 protein (p.Gln30Arg). (less)
|
|
Uncertain Significance
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004842167.1
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)
|
Comment:
This missense variant replaces glutamine with arginine at codon 30 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces glutamine with arginine at codon 30 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/245770 chromosomes 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)
Number of individuals with the variant: 1
|
|
Uncertain significance
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002519147.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Uncertain significance
(Apr 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004019849.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
|
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 |
---|---|---|---|---|
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Determinants of protein function revealed by combinatorial entropy optimization. | Reva B | Genome biology | 2007 | PMID: 17976239 |
Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. | Guarné A | The EMBO journal | 2001 | PMID: 11574484 |
Text-mined citations for rs56203955 ...
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.