This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 480 of the PMS2 protein (p.Gly480Arg). This variant is present in population databases (rs146848345, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or unspecified cancer (PMID: 31386297, 35449176). ClinVar contains an entry for this variant (Variation ID: 141000). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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.
ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.1438G>C (p.Gly480Arg)
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.
(7)
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.
Uncertain significance
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000535.7(PMS2):c.1438G>C (p.Gly480Arg)
Variation ID: 141000 Accession: VCV000141000.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p22.1 7: 5987327 (GRCh38) [ NCBI UCSC ] 7: 6026958 (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 Aug 6, 2014 Sep 16, 2024 Jul 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000535.7:c.1438G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Gly480Arg missense NM_001322003.2:c.1033G>C NP_001308932.1:p.Gly345Arg missense NM_001322004.2:c.1033G>C NP_001308933.1:p.Gly345Arg missense NM_001322005.2:c.1033G>C NP_001308934.1:p.Gly345Arg missense NM_001322006.2:c.1282G>C NP_001308935.1:p.Gly428Arg missense NM_001322007.2:c.1120G>C NP_001308936.1:p.Gly374Arg missense NM_001322008.2:c.1120G>C NP_001308937.1:p.Gly374Arg missense NM_001322009.2:c.1033G>C NP_001308938.1:p.Gly345Arg missense NM_001322010.2:c.877G>C NP_001308939.1:p.Gly293Arg missense NM_001322011.2:c.505G>C NP_001308940.1:p.Gly169Arg missense NM_001322012.2:c.505G>C NP_001308941.1:p.Gly169Arg missense NM_001322013.2:c.865G>C NP_001308942.1:p.Gly289Arg missense NM_001322014.2:c.1438G>C NP_001308943.1:p.Gly480Arg missense NM_001322015.2:c.1129G>C NP_001308944.1:p.Gly377Arg missense NR_136154.1:n.1525G>C non-coding transcript variant NC_000007.14:g.5987327C>G NC_000007.13:g.6026958C>G NG_008466.1:g.26780G>C LRG_161:g.26780G>C LRG_161t1:c.1438G>C - Protein change
- G480R, G169R, G428R, G289R, G345R, G377R, G293R, G374R
- Other names
- -
- Canonical SPDI
- NC_000007.14:5987326:C:G
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 | ||
|---|---|---|---|---|---|---|
| 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 |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 15, 2023 | RCV000129313.8 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 9, 2024 | RCV000589892.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 25, 2024 | RCV000629794.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Mar 18, 2022 | RCV002505103.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 2, 2023 | RCV003997493.2 |
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
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000750750.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 480 of the PMS2 protein (p.Gly480Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 480 of the PMS2 protein (p.Gly480Arg). This variant is present in population databases (rs146848345, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or unspecified cancer (PMID: 31386297, 35449176). ClinVar contains an entry for this variant (Variation ID: 141000). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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. (less)
|
|
|
Uncertain significance
(Mar 15, 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: SCV000911857.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 480 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with arginine at codon 480 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals who met criteria for BRCA1/2 or Lynch syndrome gene testing (PMID: 25318351). This variant has been identified in 2/251486 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
(Jun 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184075.4
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.G480R variant (also known as c.1438G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide … (more)
The p.G480R variant (also known as c.1438G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1438. The glycine at codon 480 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified once and classified as a variant of unknown significance in a cohort of 105 patients undergoing multi-gene panel testing (Yorczyk A et al, Clin. Genet. 2015 Sep; 88(3):278-82). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Jul 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000279140.13
First in ClinVar: May 29, 2016 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25318351, 31386297, 28873162, 35449176) (less)
|
|
|
Uncertain significance
(Feb 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697297.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PMS2 c.1438G>C (p.Gly480Arg) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant … (more)
Variant summary: The PMS2 c.1438G>C (p.Gly480Arg) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant was reported in the literature in a patient being tested for HBOC or Lynch Syndrome, without strong evidence for causality (Yorczyk_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as VUS. (less)
|
|
|
Uncertain significance
(Mar 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 4
Mismatch repair cancer syndrome 4
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002815788.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain Significance
(Nov 02, 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: SCV004844214.1
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 glycine with arginine at codon 480 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with arginine at codon 480 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals who met criteria for BRCA1/2 or Lynch syndrome gene testing (PMID: 25318351). This variant has been identified in 2/251486 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: 2
|
Comment:
Comment:
This missense variant replaces glycine with arginine at codon 480 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals who met criteria for BRCA1/2 or Lynch syndrome gene testing (PMID: 25318351). This variant has been identified in 2/251486 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.
Comment:
The p.G480R variant (also known as c.1438G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1438. The glycine at codon 480 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified once and classified as a variant of unknown significance in a cohort of 105 patients undergoing multi-gene panel testing (Yorczyk A et al, Clin. Genet. 2015 Sep; 88(3):278-82). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25318351, 31386297, 28873162, 35449176)
Comment:
Variant summary: The PMS2 c.1438G>C (p.Gly480Arg) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant was reported in the literature in a patient being tested for HBOC or Lynch Syndrome, without strong evidence for causality (Yorczyk_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as VUS.
Comment:
This missense variant replaces glycine with arginine at codon 480 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals who met criteria for BRCA1/2 or Lynch syndrome gene testing (PMID: 25318351). This variant has been identified in 2/251486 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.
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 sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 480 of the PMS2 protein (p.Gly480Arg). This variant is present in population databases (rs146848345, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or unspecified cancer (PMID: 31386297, 35449176). ClinVar contains an entry for this variant (Variation ID: 141000). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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.
Comment:
This missense variant replaces glycine with arginine at codon 480 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals who met criteria for BRCA1/2 or Lynch syndrome gene testing (PMID: 25318351). This variant has been identified in 2/251486 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.
Comment:
The p.G480R variant (also known as c.1438G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1438. The glycine at codon 480 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified once and classified as a variant of unknown significance in a cohort of 105 patients undergoing multi-gene panel testing (Yorczyk A et al, Clin. Genet. 2015 Sep; 88(3):278-82). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25318351, 31386297, 28873162, 35449176)
Comment:
Variant summary: The PMS2 c.1438G>C (p.Gly480Arg) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant was reported in the literature in a patient being tested for HBOC or Lynch Syndrome, without strong evidence for causality (Yorczyk_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as VUS.
Comment:
This missense variant replaces glycine with arginine at codon 480 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals who met criteria for BRCA1/2 or Lynch syndrome gene testing (PMID: 25318351). This variant has been identified in 2/251486 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients. | Hu L | NPJ breast cancer | 2022 | PMID: 35449176 |
| Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients. | Kiyozumi Y | Cancer medicine | 2019 | PMID: 31386297 |
| Use of panel tests in place of single gene tests in the cancer genetics clinic. | Yorczyk A | Clinical genetics | 2015 | PMID: 25318351 |
Text-mined citations for rs146848345 ...
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 Nov 19, 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.