VCV000182805.18 - ClinVar

NM_000535.7(PMS2):c.149G>A (p.Gly50Asp)

Germline

Classification

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)

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

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.149G>A (p.Gly50Asp)

Variation ID: 182805 Accession: VCV000182805.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 6005906 (GRCh38) [ NCBI UCSC ] 7: 6045537 (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	Dec 26, 2017	Sep 16, 2024	Apr 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.149G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000526.2:p.Gly50Asp	missense
NM_001322003.2:c.-257G>A		5 prime UTR
NM_001322004.2:c.-242-1848G>A		intron variant
NM_001322005.2:c.-257G>A		5 prime UTR
NM_001322006.2:c.149G>A	NP_001308935.1:p.Gly50Asp	missense
NM_001322007.2:c.-67G>A		5 prime UTR
NM_001322008.2:c.-52-1848G>A		intron variant
NM_001322009.2:c.-257G>A		5 prime UTR
NM_001322010.2:c.-242-1848G>A		intron variant
NM_001322011.2:c.-736G>A		5 prime UTR
NM_001322012.2:c.-736G>A		5 prime UTR
NM_001322013.2:c.-257G>A		5 prime UTR
NM_001322014.2:c.149G>A	NP_001308943.1:p.Gly50Asp	missense
NM_001322015.2:c.-336G>A		5 prime UTR
NR_136154.1:n.236G>A		non-coding transcript variant
NC_000007.14:g.6005906C>T
NC_000007.13:g.6045537C>T
NG_008466.1:g.8201G>A
NG_050738.1:g.1656C>T
LRG_161:g.8201G>A
LRG_161t1:c.149G>A

... more HGVS ... less HGVS

Protein change

G50D

Other names

p.G50D:GGT>GAT

Canonical SPDI

NC_000007.14:6005905:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00003

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA009773 dbSNP: rs539285592 VarSome

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
Gene	OMIM	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.
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000571665.8
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Aug 31, 2022	RCV000542157.4
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV000586511.5
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 15, 2023	RCV003998526.2
Lynch syndrome 4	Uncertain significance (1)	criteria provided, single submitter	Mar 19, 2024	RCV004567226.1

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.
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000670761.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 27978560 Comment: The p.G50D variant (also known as c.149G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide … (more) The p.G50D variant (also known as c.149G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide position 149. The glycine at codon 50 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in 1/450 individuals diagnosed with colorectal cancer under age 50 and undergoing panel testing for 25 cancer susceptibility genes (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Mar 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005056390.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Aug 31, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000625530.3 First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 27978560 Comment: This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 50 of the PMS2 protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 50 of the PMS2 protein (p.Gly50Asp). This variant is present in population databases (rs539285592, gnomAD 0.003%). This missense change has been observed in individual(s) with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 182805). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 (Nov 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000686130.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 27978560 Comment: This missense variant replaces glycine with aspartic acid at codon 50 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact … (more) This missense variant replaces glycine with aspartic acid at codon 50 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 been reported in an individual affected with early onset rectal cancer whose tumor was mismatch repair proficient (PMID: 27978560). This variant has been identified in 2/245762 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 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004842153.1 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)	Number of individuals with the variant: 1
Uncertain significance (Oct 06, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697298.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant summary: The PMS2 c.149G>A (p.Gly50Asp) variant located in the Histidine kinase-like ATPase, C-terminal domain (via InterPro) causes a missense change involving a conserved nucleotide … (more) Variant summary: The PMS2 c.149G>A (p.Gly50Asp) variant located in the Histidine kinase-like ATPase, C-terminal domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/115490 (1/57745), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMS2 variant of 1/8802. In addition, one clinical diagnostic laboratories has classified this variant as "uncertain significance." The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. (less)
Uncertain significance (Apr 01, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000211582.16 First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with rectal cancer; however, tumor studies were discordant (PMID: 27978560); This variant is associated with the following publications: (PMID: 11574484, 27978560) (less)

Comment:

The p.G50D variant (also known as c.149G>A), located in coding exon 2 of the PMS2 gene, results from a G to A substitution at nucleotide position 149. The glycine at codon 50 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in 1/450 individuals diagnosed with colorectal cancer under age 50 and undergoing panel testing for 25 cancer susceptibility genes (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 50 of the PMS2 protein (p.Gly50Asp). This variant is present in population databases (rs539285592, gnomAD 0.003%). This missense change has been observed in individual(s) with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 182805). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 aspartic acid at codon 50 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 been reported in an individual affected with early onset rectal cancer whose tumor was mismatch repair proficient (PMID: 27978560). This variant has been identified in 2/245762 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:

Variant summary: The PMS2 c.149G>A (p.Gly50Asp) variant located in the Histidine kinase-like ATPase, C-terminal domain (via InterPro) causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/115490 (1/57745), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMS2 variant of 1/8802. In addition, one clinical diagnostic laboratories has classified this variant as "uncertain significance." The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with rectal cancer; however, tumor studies were discordant (PMID: 27978560); This variant is associated with the following publications: (PMID: 11574484, 27978560)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.	Pearlman R	JAMA oncology	2017	PMID: 27978560

Text-mined citations for rs539285592 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000535.7(PMS2):c.149G>A (p.Gly50Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs539285592 ...