VCV000187605.29 - ClinVar

NM_000535.7(PMS2):c.113C>T (p.Ala38Val)

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.

(11)

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.113C>T (p.Ala38Val)

Variation ID: 187605 Accession: VCV000187605.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 6005942 (GRCh38) [ NCBI UCSC ] 7: 6045573 (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	Feb 19, 2018	Oct 8, 2024	Jan 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.113C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000526.2:p.Ala38Val	missense
NM_001322003.2:c.-293C>T		5 prime UTR
NM_001322004.2:c.-242-1884C>T		intron variant
NM_001322005.2:c.-293C>T		5 prime UTR
NM_001322006.2:c.113C>T	NP_001308935.1:p.Ala38Val	missense
NM_001322007.2:c.-103C>T		5 prime UTR
NM_001322008.2:c.-52-1884C>T		intron variant
NM_001322009.2:c.-293C>T		5 prime UTR
NM_001322010.2:c.-242-1884C>T		intron variant
NM_001322011.2:c.-772C>T		5 prime UTR
NM_001322012.2:c.-772C>T		5 prime UTR
NM_001322013.2:c.-293C>T		5 prime UTR
NM_001322014.2:c.113C>T	NP_001308943.1:p.Ala38Val	missense
NM_001322015.2:c.-372C>T		5 prime UTR
NR_136154.1:n.200C>T		non-coding transcript variant
NC_000007.14:g.6005942G>A
NC_000007.13:g.6045573G>A
NG_008466.1:g.8165C>T
NG_050738.1:g.1692G>A
LRG_161:g.8165C>T
LRG_161t1:c.113C>T

... more HGVS ... less HGVS

Protein change

A38V

Other names

Canonical SPDI

NC_000007.14:6005941:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00014

1000 Genomes Project 30x 0.00016

Links

ClinGen: CA009226 dbSNP: rs148270248 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	Nov 30, 2023	RCV000167349.11
Hereditary nonpolyposis colorectal neoplasms	Uncertain significance (1)	criteria provided, single submitter	Jan 10, 2024	RCV000229343.11
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 28, 2023	RCV000759911.8
Lynch syndrome 4	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 11, 2023	RCV000987853.2
Breast and/or ovarian cancer	Uncertain significance (1)	criteria provided, single submitter	Dec 7, 2021	RCV003150031.2
Lynch syndrome 4 Mismatch repair cancer syndrome 4	Uncertain significance (1)	criteria provided, single submitter	Aug 25, 2021	RCV002478518.1
Lynch syndrome	Uncertain significance (1)	criteria provided, single submitter	Dec 18, 2023	RCV003995585.2
PMS2-related disorder	Uncertain significance (1)	no assertion criteria provided	Jul 10, 2024	RCV004724963.1

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 (Oct 24, 2023)	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: SCV000218201.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: The p.A38V variant (also known as c.113C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide … (more) The p.A38V variant (also known as c.113C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide position 113. The alanine at codon 38 is replaced by valine, an amino acid with similar properties. 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 (Dec 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838400.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Uncertain significance (Oct 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004205395.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137332.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Jan 27, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889606.3 First in ClinVar: Mar 15, 2019 Last updated: Jan 01, 2022
Uncertain significance (Nov 30, 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: SCV000686095.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 26689913‚ 33821390‚ 35402282‚ 36243179 Comment: This missense variant replaces alanine with valine at codon 38 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces alanine with valine at codon 38 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with low grade glioma, breast or thyroid cancers (PMID: 26689913, 33821390, 35402282) as well as unaffected individuals (PMID: 36243179). This variant has been identified in 5/245784 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 (Dec 18, 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: SCV004842160.1 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)	Publications: PubMed (4) PubMed: 26689913‚ 33821390‚ 35402282‚ 36243179 Comment: This missense variant replaces alanine with valine at codon 38 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces alanine with valine at codon 38 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with low grade glioma, breast or thyroid cancers (PMID: 26689913, 33821390, 35402282) as well as unaffected individuals (PMID: 36243179). This variant has been identified in 5/245784 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: 5
Uncertain significance (Aug 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Mismatch repair cancer syndrome 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002784078.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Aug 28, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001797260.3 First in ClinVar: Aug 21, 2021 Last updated: Aug 31, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, glioma, papillary thyroid cancer, … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, glioma, papillary thyroid cancer, and pituitary adenoma (Lu et al., 2015; Cetani et al., 2019; Mio et al., 2021; Abdel-Razeq et al., 2022); This variant is associated with the following publications: (PMID: 26689913, 31486992, 33821390, 35402282, 11574484, 36243179) (less)
Uncertain significance (Jan 10, 2024)	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: SCV000285045.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 38 of the PMS2 protein (p.Ala38Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 38 of the PMS2 protein (p.Ala38Val). This variant is present in population databases (rs148270248, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This missense change has been observed to co-occur in individuals with a different variant in PMS2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 187605). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. 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 (Jul 10, 2024)	no assertion criteria provided Method: clinical testing	PMS2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005339970.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PMS2 c.113C>T variant is predicted to result in the amino acid substitution p.Ala38Val. To our knowledge, this variant has not been reported in the … (more) The PMS2 c.113C>T variant is predicted to result in the amino acid substitution p.Ala38Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187605/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Comment:

The p.A38V variant (also known as c.113C>T), located in coding exon 2 of the PMS2 gene, results from a C to T substitution at nucleotide position 113. The alanine at codon 38 is replaced by valine, an amino acid with similar properties. 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 missense variant replaces alanine with valine at codon 38 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with low grade glioma, breast or thyroid cancers (PMID: 26689913, 33821390, 35402282) as well as unaffected individuals (PMID: 36243179). This variant has been identified in 5/245784 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:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, glioma, papillary thyroid cancer, and pituitary adenoma (Lu et al., 2015; Cetani et al., 2019; Mio et al., 2021; Abdel-Razeq et al., 2022); This variant is associated with the following publications: (PMID: 26689913, 31486992, 33821390, 35402282, 11574484, 36243179)

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 38 of the PMS2 protein (p.Ala38Val). This variant is present in population databases (rs148270248, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This missense change has been observed to co-occur in individuals with a different variant in PMS2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 187605). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. 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:

The PMS2 c.113C>T variant is predicted to result in the amino acid substitution p.Ala38Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187605/?new_evidence=true). 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

Title	Author	Journal	Year	Link
Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer.	Okawa Y	Journal of hepatology	2023	PMID: 36243179
Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives.	Abdel-Razeq H	Frontiers in oncology	2022	PMID: 35402282
Rare germline variants in DNA repair-related genes are accountable for papillary thyroid cancer susceptibility.	Mio C	Endocrine	2021	PMID: 33821390
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868

Text-mined citations for rs148270248 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000535.7(PMS2):c.113C>T (p.Ala38Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148270248 ...