VCV000041707.65 - ClinVar

NM_000535.7(PMS2):c.1789A>T (p.Thr597Ser)

Germline

Top reviewed classifications are shown here.

Submission summary:

28 submissions

28 submitters

8 conditions

Reviewed by expert panel

Benign

Oct 2014 by International …

for Lynch syndrome 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000535.7(PMS2):c.1789A>T (p.Thr597Ser)

Variation ID: 41707 Accession: VCV000041707.65

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.1 7: 5986976 (GRCh38) [ NCBI UCSC ] 7: 6026607 (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	Apr 12, 2013	Oct 20, 2024	Oct 10, 2014

HGVS

Nucleotide	Protein	Molecular consequence
NM_000535.7:c.1789A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000526.2:p.Thr597Ser	missense
NM_001322003.2:c.1384A>T	NP_001308932.1:p.Thr462Ser	missense
NM_001322004.2:c.1384A>T	NP_001308933.1:p.Thr462Ser	missense
NM_001322005.2:c.1384A>T	NP_001308934.1:p.Thr462Ser	missense
NM_001322006.2:c.1633A>T	NP_001308935.1:p.Thr545Ser	missense
NM_001322007.2:c.1471A>T	NP_001308936.1:p.Thr491Ser	missense
NM_001322008.2:c.1471A>T	NP_001308937.1:p.Thr491Ser	missense
NM_001322009.2:c.1384A>T	NP_001308938.1:p.Thr462Ser	missense
NM_001322010.2:c.1228A>T	NP_001308939.1:p.Thr410Ser	missense
NM_001322011.2:c.856A>T	NP_001308940.1:p.Thr286Ser	missense
NM_001322012.2:c.856A>T	NP_001308941.1:p.Thr286Ser	missense
NM_001322013.2:c.1216A>T	NP_001308942.1:p.Thr406Ser	missense
NM_001322014.2:c.1789A>T	NP_001308943.1:p.Thr597Ser	missense
NM_001322015.2:c.1480A>T	NP_001308944.1:p.Thr494Ser	missense
NR_136154.1:n.1876A>T		non-coding transcript variant
NC_000007.14:g.5986976T>A
NC_000007.13:g.6026607T>A
NG_008466.1:g.27131A>T
LRG_161:g.27131A>T
LRG_161t1:c.1789A>T
	P54278:p.Thr597Ser

... more HGVS ... less HGVS

Protein change

T597S, T410S, T462S, T491S, T494S, T286S, T406S, T545S

Other names

p.T597S:ACT>TCT

Canonical SPDI

NC_000007.14:5986975:T: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.

0.00280 (A)

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

1000 Genomes Project 0.00280

1000 Genomes Project 30x 0.00328

Exome Aggregation Consortium (ExAC) 0.00821

The Genome Aggregation Database (gnomAD), exomes 0.00828

Trans-Omics for Precision Medicine (TOPMed) 0.00881

The Genome Aggregation Database (gnomAD) 0.01006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01161

Links

ClinGen: CA010234 UniProtKB: P54278#VAR_012972 dbSNP: rs1805318 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.
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000034622.36
not specified	Benign (10)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000121842.34
Hereditary cancer-predisposing syndrome	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 4, 2016	RCV000129319.14
Lynch syndrome 1	Benign (2)	reviewed by expert panel	Oct 10, 2014	RCV000144655.9
Lynch syndrome 4	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV000412079.20
Hereditary nonpolyposis colorectal neoplasms	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001080576.16
Carcinoma of colon	Benign (1)	no assertion criteria provided	-	RCV001357844.9
Lynch syndrome	Benign (1)	criteria provided, single submitter	Feb 5, 2024	RCV003996172.2

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.
Benign (Oct 10, 2014)	reviewed by expert panel (Guidelines v1.9) Method: research	Lynch syndrome 1 Affected status: unknown Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000108314.3 First in ClinVar: Dec 19, 2013 Last updated: Oct 19, 2014	Other databases http://www.insight-database.org/… http://www.insight-database.org/classifications/?gene=PMS2&variant=c.1621A%3EC Comment: MAF >1%
Benign (Nov 11, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000171034.10 First in ClinVar: Jun 23, 2014 Last updated: Feb 19, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jun 24, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225236.5 First in ClinVar: Jun 28, 2015 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMS2 Number of individuals with the variant: 6 Sex: mixed
Benign (Nov 21, 2014)	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: SCV000537366.1 First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016
Likely benign (Jan 24, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001326299.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 19389263‚ 11793469 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Aug 15, 2023)	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: SCV002550703.4 First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023
Benign (Nov 17, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001156611.6 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Benign (Feb 01, 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: SCV000153971.12 First in ClinVar: Jun 23, 2014 Last updated: Feb 28, 2024
Benign (Feb 04, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Vantari Genetics Accession: SCV000267072.1 First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000304724.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Mar 07, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Lynch syndrome 4 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743778.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017
Benign (Jun 01, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488727.2 First in ClinVar: Jan 09, 2017 Last updated: Dec 24, 2022	Publications: PubMed (13) PubMed: 22949387‚ 20205264‚ 24027009‚ 16472587‚ 16619239‚ 21239990‚ 10480359‚ 22703879‚ 24728327‚ 22290698‚ 18768816‚ 11793469‚ 23709753
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 4 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016595.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (May 11, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Lynch syndrome 4 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004044343.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Comment: This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence … (more) This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)
Benign (Feb 05, 2024)	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: SCV004844134.1 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: 2525
Benign (Nov 18, 2014)	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: SCV000184082.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002545494.16 First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024	Comment: PMS2: BP4, BS1, BS2 Number of individuals with the variant: 74
Likely benign (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Lynch syndrome I Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189982.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014	Publications: PubMed (6) PubMed: 22703879‚ 22949387‚ 10480359‚ 9683794‚ 22290698‚ 23709753
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906297.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921976.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
no known pathogenicity (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043421.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Benign. Number of individuals with the variant: 15 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000691966.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Benign (Jun 20, 2016)	no assertion criteria provided (ACGS Guidelines, 2013) Method: clinical testing	Lynch syndrome 4 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000745838.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017
Benign (Jan 12, 2018)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000788110.1 First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016
Benign (-)	no assertion criteria provided Method: clinical testing	Carcinoma of colon Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001553433.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The PMS2 p.Thr597Ser variant was identified in 27 of 746 proband chromosomes (frequency: 0.036) from Dutch, American, British and French individuals or families with HNPCC, … (more) The PMS2 p.Thr597Ser variant was identified in 27 of 746 proband chromosomes (frequency: 0.036) from Dutch, American, British and French individuals or families with HNPCC, early-onset CRC, MAP or breast cancer and was identified in 37 of 1922 chromosomes (frequency: 0.02) from healthy individuals (Hendriks 2006, Balogh 2006, Lefevre 2012). The variant was also identified in dbSNP (ID: rs1805318) as "With Likely benign allele", ClinVar (classified 10x as benign: InSiGHT, Invitae, GeneDx, Ambry Genetics, Emory Genetics Laboratory, Vantari Genetics, PreventionGenetics, Counsyl, Color Genomics, Biesecker Lab/NIH; 1x likely benign: Pathway Genomics; 1x not provided: ITMI), Clinvitae (7x), MutDB (UniProt Category: Polymorphism), Insight Colon Cancer Gene Variant Database (12x not pathogenic), and the Mismatch Repair Genes Variant Database (3x). The variant was not identified in GeneInsight-COGR, COSMIC, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 2380 of 277222 chromosomes (15 homozygous) at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 1893 of 126716 chromosomes (freq: 0.015) Functional data suggest conflicting effects for this variant. An in vitro pull-down assay demonstrating that this SNP results in defective protein-protein interaction with MLH1, despite the fact that the alteration is outside the putative MLH1 interaction domain, suggests an increased risk factor for tumourigenesis in HNPCC. However, a cell-free MMR functional assay of VUS in PMS2 using MLH1/PMS2 heterodimer to restore a plasmid restriction enzyme site demonstrated 70% activity and was not considered MMR-deficient relative to known pathogenic controls. The p.Thr597Ser residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798033.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958881.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000086040.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

The PMS2 p.Thr597Ser variant was identified in 27 of 746 proband chromosomes (frequency: 0.036) from Dutch, American, British and French individuals or families with HNPCC, early-onset CRC, MAP or breast cancer and was identified in 37 of 1922 chromosomes (frequency: 0.02) from healthy individuals (Hendriks 2006, Balogh 2006, Lefevre 2012). The variant was also identified in dbSNP (ID: rs1805318) as "With Likely benign allele", ClinVar (classified 10x as benign: InSiGHT, Invitae, GeneDx, Ambry Genetics, Emory Genetics Laboratory, Vantari Genetics, PreventionGenetics, Counsyl, Color Genomics, Biesecker Lab/NIH; 1x likely benign: Pathway Genomics; 1x not provided: ITMI), Clinvitae (7x), MutDB (UniProt Category: Polymorphism), Insight Colon Cancer Gene Variant Database (12x not pathogenic), and the Mismatch Repair Genes Variant Database (3x). The variant was not identified in GeneInsight-COGR, COSMIC, Zhejiang Colon Cancer Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 2380 of 277222 chromosomes (15 homozygous) at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 1893 of 126716 chromosomes (freq: 0.015) Functional data suggest conflicting effects for this variant. An in vitro pull-down assay demonstrating that this SNP results in defective protein-protein interaction with MLH1, despite the fact that the alteration is outside the putative MLH1 interaction domain, suggests an increased risk factor for tumourigenesis in HNPCC. However, a cell-free MMR functional assay of VUS in PMS2 using MLH1/PMS2 heterodimer to restore a plasmid restriction enzyme site demonstrated 70% activity and was not considered MMR-deficient relative to known pathogenic controls. The p.Thr597Ser residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene.	Drost M	Human mutation	2013	PMID: 24027009
Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.	Borràs E	Journal of medical genetics	2013	PMID: 23709753
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.	Thompson BA	Human mutation	2013	PMID: 22949387
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879
Classification of mismatch repair gene missense variants with PON-MMR.	Ali H	Human mutation	2012	PMID: 22290698
Integrated analysis of unclassified variants in mismatch repair genes.	Pastrello C	Genetics in medicine : official journal of the American College of Medical Genetics	2011	PMID: 21239990
Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes.	Vaughn CP	Human mutation	2010	PMID: 20205264
Investigation on the role of nsSNPs in HNPCC genes--a bioinformatics approach.	Doss CG	Journal of biomedical science	2009	PMID: 19389263
Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q.	Marinovic-Terzic I	Proceedings of the National Academy of Sciences of the United States of America	2008	PMID: 18768816
Long-range PCR facilitates the identification of PMS2-specific mutations.	Clendenning M	Human mutation	2006	PMID: 16619239
Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome).	Hendriks YM	Gastroenterology	2006	PMID: 16472587
Polymorphisms and HNPCC: PMS2-MLH1 protein interactions diminished by single nucleotide polymorphisms.	Yuan ZQ	Human mutation	2002	PMID: 11793469
Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.	Wang Q	Human genetics	1999	PMID: 10480359
Lack of PMS2 gene-truncating mutations in patients with hereditary colorectal cancer.	Viel A	International journal of oncology	1998	PMID: 9683794
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMS2	-	-	-	-
http://www.insight-database.org/classifications/?gene=PMS2&variant=c.1621A%3EC	-	-	-	-
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Text-mined citations for rs1805318 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000535.7(PMS2):c.1789A>T (p.Thr597Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1805318 ...