ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.2445G>A (p.Ser815=)
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(6); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000535.7(PMS2):c.2445G>A (p.Ser815=)
Variation ID: 184485 Accession: VCV000184485.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 5977588 (GRCh38) [ NCBI UCSC ] 7: 6017219 (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 Jul 1, 2016 May 12, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000535.7:c.2445G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Ser815= synonymous NM_001322003.2:c.2040G>A NP_001308932.1:p.Ser680= synonymous NM_001322004.2:c.2040G>A NP_001308933.1:p.Ser680= synonymous NM_001322005.2:c.2040G>A NP_001308934.1:p.Ser680= synonymous NM_001322006.2:c.2289G>A NP_001308935.1:p.Ser763= synonymous NM_001322007.2:c.2127G>A NP_001308936.1:p.Ser709= synonymous NM_001322008.2:c.2127G>A NP_001308937.1:p.Ser709= synonymous NM_001322009.2:c.2073G>A NP_001308938.1:p.Ser691= synonymous NM_001322010.2:c.1884G>A NP_001308939.1:p.Ser628= synonymous NM_001322011.2:c.1512G>A NP_001308940.1:p.Ser504= synonymous NM_001322012.2:c.1512G>A NP_001308941.1:p.Ser504= synonymous NM_001322013.2:c.1872G>A NP_001308942.1:p.Ser624= synonymous NM_001322014.2:c.2478G>A NP_001308943.1:p.Ser826= synonymous NM_001322015.2:c.2136G>A NP_001308944.1:p.Ser712= synonymous NR_136154.1:n.2489G>A non-coding transcript variant NC_000007.14:g.5977588C>T NC_000007.13:g.6017219C>T NG_008466.1:g.36519G>A LRG_161:g.36519G>A LRG_161t1:c.2445G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000007.14:5977587: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.
The Genome Aggregation Database (gnomAD), exomes 0.00011
The Genome Aggregation Database (gnomAD) 0.00012
Exome Aggregation Consortium (ExAC) 0.00014
1000 Genomes Project 30x 0.00016
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
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 |
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. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 22, 2023 | RCV000163748.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2018 | RCV000987819.13 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 1, 2024 | RCV000859086.21 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 3, 2022 | RCV001420820.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV001084869.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 30, 2022 | RCV003492679.1 |
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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Benign
(Mar 03, 2015)
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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: SCV001862613.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
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Uncertain significance
(Dec 13, 2022)
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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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Mendelics
Accession: SCV001137277.2
First in ClinVar: Jan 09, 2020 Last updated: Dec 17, 2022 |
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Likely benign
(Nov 29, 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: SCV000214324.7
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)
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Likely benign
(Jan 01, 2024)
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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: SCV004701108.3
First in ClinVar: Mar 10, 2024 Last updated: May 12, 2024 |
Comment:
PMS2: BP4, BP7
Number of individuals with the variant: 1
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Uncertain significance
(Jan 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001320886.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Aug 26, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530308.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The PMS2 c.2445G>A (p.S815=) variant has been reported variant has not been reported in literature to our knowledge. This variant was observed in 11/30100 chromosomes … (more)
The PMS2 c.2445G>A (p.S815=) variant has been reported variant has not been reported in literature to our knowledge. This variant was observed in 11/30100 chromosomes in the Latino population, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 184485). This variant is the last nucleotide of exon 14 and computational tools suggest that this variant may weaken the donnor splice site, though these predictions have not been confirmed by functional studies. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
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Likely benign
(Nov 03, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623200.2
First in ClinVar: May 23, 2021 Last updated: Dec 24, 2022 |
Comment:
Variant summary: PMS2 c.2445G>A (p.Ser815Ser) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a … (more)
Variant summary: PMS2 c.2445G>A (p.Ser815Ser) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 194842 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. However, this data should be interpreted with caution as the sequencing technology utilized cannot rule out possible pseudogene interference due to sequence overlap in this region. To our knowledge, c.2445G>A has not been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Feb 07, 2023)
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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: SCV001134596.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00037 (11/30100 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for … (more)
The frequency of this variant in the general population, 0.00037 (11/30100 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast, ovarian or prostate cancer (PMID: 34371384 (2021)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper PMS2 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239596.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Jan 18, 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: SCV000255294.9
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
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Uncertain significance
(Mar 22, 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: SCV004358982.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This synonymous variant is located at the last nucleotide of exon 14 of the PMS2 gene. To our knowledge, RNA studies have not been reported … (more)
This synonymous variant is located at the last nucleotide of exon 14 of the PMS2 gene. To our knowledge, RNA studies have not been reported for this variant. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 25/224802 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)
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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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Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge. | Bono M | ESMO open | 2021 | PMID: 34371384 |
Text-mined citations for rs753199796 ...
HelpRecord last updated May 27, 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.