VCV000185828.18 - ClinVar

NM_000535.7(PMS2):c.*3G>A

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(5); Benign(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000535.7(PMS2):c.*3G>A

Variation ID: 185828 Accession: VCV000185828.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 5973396 (GRCh38) [ NCBI UCSC ] 7: 6013027 (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	Sep 30, 2017	Jan 19, 2025	Nov 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.*3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001322003.2:c.*3G>A		3 prime UTR
NM_001322004.2:c.*3G>A		3 prime UTR
NM_001322005.2:c.*3G>A		3 prime UTR
NM_001322006.2:c.*3G>A		3 prime UTR
NM_001322007.2:c.*3G>A		3 prime UTR
NM_001322008.2:c.*3G>A		3 prime UTR
NM_001322009.2:c.*3G>A		3 prime UTR
NM_001322010.2:c.*3G>A		3 prime UTR
NM_001322011.2:c.*3G>A		3 prime UTR
NM_001322012.2:c.*3G>A		3 prime UTR
NM_001322013.2:c.*3G>A		3 prime UTR
NM_001322014.2:c.*3G>A		3 prime UTR
NM_001322015.2:c.*3G>A		3 prime UTR
NR_136154.1:n.2636G>A		non-coding transcript variant
NC_000007.14:g.5973396C>T
NC_000007.13:g.6013027C>T
NG_008466.1:g.40711G>A
LRG_161:g.40711G>A
LRG_161t1:c.*3G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000007.14:5973395: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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA012074 dbSNP: rs776493195 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	5333	5436

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	Mar 13, 2023	RCV000165323.6
not specified	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Apr 18, 2024	RCV000506179.6
not provided	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Aug 1, 2024	RCV000589954.10
PMS2-related disorder	Uncertain significance (1)	no assertion criteria provided	Apr 19, 2024	RCV004742292.1
Hereditary breast ovarian cancer syndrome	Uncertain significance (1)	criteria provided, single submitter	Nov 19, 2024	RCV004786465.1

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.
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001894414.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Likely benign (Feb 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004243273.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Uncertain significance (Mar 06, 2017)	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: SCV000216045.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: The c.3G>A variant is located in the 3' untranslated region (3’ UTR) of the PMS2 gene. This variant results from a G to A substitution … (more) The c.3G>A variant is located in the 3' untranslated region (3’ UTR) of the PMS2 gene. This variant results from a G to A substitution 3 nucleotides downstream of the last translated codon. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Apr 18, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697274.4 First in ClinVar: Mar 17, 2018 Last updated: Jul 15, 2024	Comment: Variant summary: PMS2 c.3G>A is located in the untranslated mRNA region downstream of the termination codon. Consensus agreement among computation tools predict no significant impact … (more) Variant summary: PMS2 c.3G>A is located in the untranslated mRNA region downstream of the termination codon. Consensus agreement among computation 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 1.5e-05 in 199080 control chromosomes in the gnomAD database, including 1 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.*3G>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 185828). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Nov 19, 2024)	criteria provided, single submitter (ClinGen PMS2 V1.0.0) Method: curation	Hereditary breast ovarian cancer syndrome Affected status: not provided Allele origin: germline	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV005400654.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: no criteria applicable
Uncertain significance (Aug 01, 2024)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889603.5 First in ClinVar: Mar 17, 2018 Last updated: Jan 19, 2025	Comment: The PMS2 c.3G>A variant has not been reported in individuals with PMS2-related conditions in the published literature. The frequency of this variant in the general … (more) The PMS2 c.3G>A variant has not been reported in individuals with PMS2-related conditions in the published literature. The frequency of this variant in the general population, 0.000041 (4/96786 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect PMS2 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Mar 13, 2023)	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: SCV004358943.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This variant is located in the 3' untranslated region of the PMS2 gene. To our knowledge, functional studies have not been reported for this variant. … (more) This variant is located in the 3' untranslated region of the PMS2 gene. 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 5/219538 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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 (Apr 19, 2024)	no assertion criteria provided Method: clinical testing	PMS2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005361452.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PMS2 c.3G>A variant is located in the 3' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant … (more) The PMS2 c.3G>A variant is located in the 3' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/185828/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

The c.*3G>A variant is located in the 3' untranslated region (3’ UTR) of the PMS2 gene. This variant results from a G to A substitution 3 nucleotides downstream of the last translated codon. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Variant summary: PMS2 c.*3G>A is located in the untranslated mRNA region downstream of the termination codon. Consensus agreement among computation 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 1.5e-05 in 199080 control chromosomes in the gnomAD database, including 1 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.*3G>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 185828). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

The PMS2 c.*3G>A variant has not been reported in individuals with PMS2-related conditions in the published literature. The frequency of this variant in the general population, 0.000041 (4/96786 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect PMS2 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This variant is located in the 3' untranslated region of the PMS2 gene. 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 5/219538 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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 PMS2 c.*3G>A variant is located in the 3' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/185828/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs776493195 ...

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 Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_000535.7(PMS2):c.*3G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs776493195 ...