The p.R169G variant (also known as c.505C>G), located in coding exon 5 of the PMS2 gene, results from a C to G substitution at nucleotide position 505. The arginine at codon 169 is replaced by glycine, an amino acid with dissimilar properties. This variant has been confirmed in trans with a PMS2 pathogenic variant in an individual diagnosed with constitutional mismatch repair deficiency syndrome (Mork ME et al. Fam Cancer, 2016 10;15:587-91). Based on internal structural analysis, R169G disrupts a conserved arginine mediating a tripartite intramolecular interaction, but there are no internally pathogenic variants nearby for comparison (D'Arcy BM et al. Mol Genet Genomic Med, 2022 Feb;10:e1908; Guarné A et al. EMBO J, 2001 Oct;20:5521-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000535.7(PMS2):c.505C>G (p.Arg169Gly)
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.
(1)
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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.
Likely pathogenic
1
criteria provided, single submitter
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.505C>G (p.Arg169Gly)
Variation ID: 1745085 Accession: VCV001745085.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7p22.1 7: 6002485 (GRCh38) [ NCBI UCSC ] 7: 6042116 (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 Nov 29, 2022 May 1, 2024 Oct 6, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000535.7:c.505C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.Arg169Gly missense NM_001018040.1:c.100C>G NP_001018050.1:p.Arg34Gly missense NM_001322003.2:c.100C>G NP_001308932.1:p.Arg34Gly missense NM_001322004.2:c.100C>G NP_001308933.1:p.Arg34Gly missense NM_001322005.2:c.100C>G NP_001308934.1:p.Arg34Gly missense NM_001322006.2:c.505C>G NP_001308935.1:p.Arg169Gly missense NM_001322007.2:c.187C>G NP_001308936.1:p.Arg63Gly missense NM_001322008.2:c.187C>G NP_001308937.1:p.Arg63Gly missense NM_001322009.2:c.100C>G NP_001308938.1:p.Arg34Gly missense NM_001322010.2:c.100C>G NP_001308939.1:p.Arg34Gly missense NM_001322011.2:c.-380C>G 5 prime UTR NM_001322012.2:c.-380C>G 5 prime UTR NM_001322013.2:c.100C>G NP_001308942.1:p.Arg34Gly missense NM_001322014.2:c.505C>G NP_001308943.1:p.Arg169Gly missense NM_001322015.2:c.196C>G NP_001308944.1:p.Arg66Gly missense NM_001406866.1:c.691C>G NP_001393795.1:p.Arg231Gly missense NM_001406868.1:c.529C>G NP_001393797.1:p.Arg177Gly missense NM_001406869.1:c.505C>G NP_001393798.1:p.Arg169Gly missense NM_001406870.1:c.505C>G NP_001393799.1:p.Arg169Gly missense NM_001406871.1:c.505C>G NP_001393800.1:p.Arg169Gly missense NM_001406872.1:c.505C>G NP_001393801.1:p.Arg169Gly missense NM_001406873.1:c.505C>G NP_001393802.1:p.Arg169Gly missense NM_001406874.1:c.505C>G NP_001393803.1:p.Arg169Gly missense NM_001406875.1:c.196C>G NP_001393804.1:p.Arg66Gly missense NM_001406876.1:c.187C>G NP_001393805.1:p.Arg63Gly missense NM_001406877.1:c.196C>G NP_001393806.1:p.Arg66Gly missense NM_001406878.1:c.196C>G NP_001393807.1:p.Arg66Gly missense NM_001406879.1:c.196C>G NP_001393808.1:p.Arg66Gly missense NM_001406880.1:c.196C>G NP_001393809.1:p.Arg66Gly missense NM_001406881.1:c.196C>G NP_001393810.1:p.Arg66Gly missense NM_001406882.1:c.196C>G NP_001393811.1:p.Arg66Gly missense NM_001406883.1:c.187C>G NP_001393812.1:p.Arg63Gly missense NM_001406884.1:c.505C>G NP_001393813.1:p.Arg169Gly missense NM_001406886.1:c.505C>G NP_001393815.1:p.Arg169Gly missense NM_001406887.1:c.100C>G NP_001393816.1:p.Arg34Gly missense NM_001406888.1:c.100C>G NP_001393817.1:p.Arg34Gly missense NM_001406889.1:c.100C>G NP_001393818.1:p.Arg34Gly missense NM_001406890.1:c.100C>G NP_001393819.1:p.Arg34Gly missense NM_001406891.1:c.100C>G NP_001393820.1:p.Arg34Gly missense NM_001406892.1:c.100C>G NP_001393821.1:p.Arg34Gly missense NM_001406893.1:c.100C>G NP_001393822.1:p.Arg34Gly missense NM_001406894.1:c.100C>G NP_001393823.1:p.Arg34Gly missense NM_001406895.1:c.100C>G NP_001393824.1:p.Arg34Gly missense NM_001406896.1:c.100C>G NP_001393825.1:p.Arg34Gly missense NM_001406897.1:c.100C>G NP_001393826.1:p.Arg34Gly missense NM_001406898.1:c.100C>G NP_001393827.1:p.Arg34Gly missense NM_001406899.1:c.100C>G NP_001393828.1:p.Arg34Gly missense NM_001406900.1:c.196C>G NP_001393829.1:p.Arg66Gly missense NM_001406901.1:c.187C>G NP_001393830.1:p.Arg63Gly missense NM_001406902.1:c.187C>G NP_001393831.1:p.Arg63Gly missense NM_001406903.1:c.187C>G NP_001393832.1:p.Arg63Gly missense NM_001406904.1:c.100C>G NP_001393833.1:p.Arg34Gly missense NM_001406905.1:c.100C>G NP_001393834.1:p.Arg34Gly missense NM_001406906.1:c.100C>G NP_001393835.1:p.Arg34Gly missense NM_001406907.1:c.100C>G NP_001393836.1:p.Arg34Gly missense NM_001406908.1:c.100C>G NP_001393837.1:p.Arg34Gly missense NM_001406909.1:c.100C>G NP_001393838.1:p.Arg34Gly missense NM_001406910.1:c.100C>G NP_001393839.1:p.Arg34Gly missense NM_001406911.1:c.100C>G NP_001393840.1:p.Arg34Gly missense NM_001406912.1:c.505C>G NP_001393841.1:p.Arg169Gly missense NR_003085.2:n.587C>G NR_136154.1:n.592C>G non-coding transcript variant NC_000007.14:g.6002485G>C NC_000007.13:g.6042116G>C NG_008466.1:g.11622C>G LRG_161:g.11622C>G LRG_161t1:c.505C>G LRG_161p1:p.Arg169Gly - Protein change
- R177G, R231G, R169G, R63G, R34G, R66G
- Other names
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- Canonical SPDI
- NC_000007.14:6002484:G:C
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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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| Likely pathogenic (1) |
criteria provided, single submitter
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Oct 6, 2023 | RCV002335777.2 |
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. |
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Likely pathogenic
(Oct 06, 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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Ambry Genetics
Accession: SCV002643571.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R169G variant (also known as c.505C>G), located in coding exon 5 of the PMS2 gene, results from a C to G substitution at nucleotide … (more)
The p.R169G variant (also known as c.505C>G), located in coding exon 5 of the PMS2 gene, results from a C to G substitution at nucleotide position 505. The arginine at codon 169 is replaced by glycine, an amino acid with dissimilar properties. This variant has been confirmed in trans with a PMS2 pathogenic variant in an individual diagnosed with constitutional mismatch repair deficiency syndrome (Mork ME et al. Fam Cancer, 2016 10;15:587-91). Based on internal structural analysis, R169G disrupts a conserved arginine mediating a tripartite intramolecular interaction, but there are no internally pathogenic variants nearby for comparison (D'Arcy BM et al. Mol Genet Genomic Med, 2022 Feb;10:e1908; Guarné A et al. EMBO J, 2001 Oct;20:5521-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
Comment:
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:
The p.R169G variant (also known as c.505C>G), located in coding exon 5 of the PMS2 gene, results from a C to G substitution at nucleotide position 505. The arginine at codon 169 is replaced by glycine, an amino acid with dissimilar properties. This variant has been confirmed in trans with a PMS2 pathogenic variant in an individual diagnosed with constitutional mismatch repair deficiency syndrome (Mork ME et al. Fam Cancer, 2016 10;15:587-91). Based on internal structural analysis, R169G disrupts a conserved arginine mediating a tripartite intramolecular interaction, but there are no internally pathogenic variants nearby for comparison (D'Arcy BM et al. Mol Genet Genomic Med, 2022 Feb;10:e1908; Guarné A et al. EMBO J, 2001 Oct;20:5521-31). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PMS2 variant results in loss of ATPase activity without compromising mismatch repair. | D'Arcy BM | Molecular genetics & genomic medicine | 2022 | PMID: 35189042 |
| Identification of a novel PMS2 alteration c.505C>G (R169G) in trans with a PMS2 pathogenic mutation in a patient with constitutional mismatch repair deficiency. | Mork ME | Familial cancer | 2016 | PMID: 27017610 |
| 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 this variant ...
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.