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NM_000535.7(PMS2):c.1437C>G (p.His479Gln)

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Interpretation:
Conflicting interpretations of pathogenicity​

Benign(10);Likely benign(4);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
22 (Most recent: Sep 30, 2021)
Last evaluated:
Mar 1, 2021
Accession:
VCV000041701.24
Variation ID:
41701
Description:
single nucleotide variant
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NM_000535.7(PMS2):c.1437C>G (p.His479Gln)

Allele ID
50140
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7p22.1
Genomic location
7: 5987328 (GRCh38) GRCh38 UCSC
7: 6026959 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P54278:p.His479Gln
NM_001322011.2:c.504C>G NP_001308940.1:p.His168Gln missense
NM_001322012.2:c.504C>G NP_001308941.1:p.His168Gln missense
... more HGVS
Protein change
H479Q, H292Q, H373Q, H427Q, H168Q, H288Q, H344Q, H376Q
Other names
p.H479Q:CAC>CAG
Canonical SPDI
NC_000007.14:5987327:G:C
Functional consequence
-
Global minor allele frequency (GMAF)
0.00280 (C)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00440
1000 Genomes Project 0.00280
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00515
Links
ClinGen: CA009671
UniProtKB: P54278#VAR_012969
dbSNP: rs63750685
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Benign/Likely benign 5 criteria provided, multiple submitters, no conflicts Mar 1, 2021 RCV000034615.15
Benign 6 criteria provided, multiple submitters, no conflicts Mar 16, 2018 RCV000121844.4
Benign 2 criteria provided, multiple submitters, no conflicts Apr 9, 2018 RCV000162366.3
Benign/Likely benign 4 criteria provided, multiple submitters, no conflicts May 28, 2019 RCV000625386.4
Benign 1 criteria provided, single submitter Dec 4, 2020 RCV001081746.2
Benign 1 criteria provided, single submitter Jul 20, 2020 RCV001282359.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Jul 2, 2018 RCV000076809.8
Benign 1 no assertion criteria provided - RCV001356193.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
PMS2 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
3065 3130

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Benign
(-)
criteria provided, single submitter
Method: clinical testing
NOT SPECIFIED
Allele origin: germline
PreventionGenetics,PreventionGenetics
Accession: SCV000304718.1
Submitted: (Apr 28, 2016)
Evidence details
Benign
(Apr 09, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000212673.5
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (7)
Comment:
In silico models in agreement (benign);Other data supporting benign classification;Other strong data supporting benign classification
Benign
(Feb 19, 2015)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000691015.1
Submitted: (Dec 21, 2017)
Evidence details
Benign
(Aug 09, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697296.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (19)
Comment:
Variant summary: The PMS2 c.1437C>G (p.His479Gln) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome. This was confirmed … (more)
Benign
(Apr 14, 2016)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal cancer type 4
Allele origin: germline
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745193.1
Submitted: (Apr 09, 2018)
Evidence details
Benign
(Nov 08, 2015)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal cancer type 4
Allele origin: germline
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745844.1
Submitted: (Apr 09, 2018)
Evidence details
Likely benign
(Jul 02, 2018)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome
Allele origin: unknown
Mendelics
Accession: SCV000838178.1
Submitted: (Aug 20, 2018)
Evidence details
Likely benign
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal cancer type 4
Allele origin: unknown
Mendelics
Accession: SCV001137298.1
Submitted: (Oct 22, 2019)
Evidence details
Likely benign
(Mar 13, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal cancer type 4
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001322473.1
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (4)
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)
Benign
(Dec 04, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000166374.10
Submitted: (Jan 07, 2021)
Evidence details
Likely benign
(Mar 01, 2021)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV000693232.10
Submitted: (Jul 04, 2021)
Evidence details
Uncertain significance
(Nov 20, 2015)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colon cancer
Allele origin: germline
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266215.1
Submitted: (Mar 03, 2016)
Evidence details
Benign
(Mar 16, 2018)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics
Accession: SCV000860370.1
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Benign
(Jul 20, 2020)
criteria provided, single submitter
Method: clinical testing
none provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
Accession: SCV000885989.2
Submitted: (Dec 11, 2020)
Evidence details
Benign
(Dec 06, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000171026.5
Submitted: (Sep 24, 2021)
Evidence details
Comment:
This variant is associated with the following publications: (PMID: 27616075, 24728327, 28874130, 31433215, 31332305)
Benign
(-)
no assertion criteria provided
Method: clinical testing
not specified
Allele origin: germline
Human Genetics - Radboudumc,Radboudumc
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955499.1
Submitted: (Sep 30, 2021)
Evidence details
no known pathogenicity
(Jul 13, 2012)
no assertion criteria provided
Method: research
not provided
Allele origin: germline
Biesecker Lab/Clinical Genomics Section,National Institutes of Health
Study: ClinSeq
Accession: SCV000043429.1
Submitted: (Jul 15, 2012)
Evidence details
Publications
PubMed (1)
Comment:
Converted during submission to Benign.
Benign
(-)
no assertion criteria provided
Method: clinical testing
Malignant tumor of breast
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: SCV001551294.1
Submitted: (Mar 31, 2021)
Evidence details
Comment:
The PMS2 p.His479Gln variant was identified in 9 of 2670 proband chromosomes (frequency: 0.003) from individuals or families with CRC and MSI positive tumors (Johnston … (more)
Benign
(-)
no assertion criteria provided
Method: clinical testing
not specified
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: SCV001920582.1
Submitted: (Sep 23, 2021)
Evidence details
Likely benign
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798176.1
Submitted: (Aug 19, 2021)
Evidence details
Benign
(-)
no assertion criteria provided
Method: clinical testing
not specified
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: SCV001905866.1
Submitted: (Sep 20, 2021)
Evidence details
not provided
(Sep 19, 2013)
no assertion provided
Method: reference population
AllHighlyPenetrant
Allele origin: germline
ITMI
Accession: SCV000086043.1
Submitted: (May 29, 2014)
Comment:
Please see associated publication for description of ethnicities
Evidence details
Publications
PubMed (1)

Functional evidence

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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.

Citations for this variant

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Title Author Journal Year Link
A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. Rossi BM BMC cancer 2017 PMID: 28874130
Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Haraldsdottir S Nature communications 2017 PMID: 28466842
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Kraus C International journal of cancer 2017 PMID: 27616075
Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records. He KY PloS one 2016 PMID: 27930734
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Lagerstedt-Robinson K Oncology reports 2016 PMID: 27601186
Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome. van der Klift HM Human mutation 2016 PMID: 27435373
Comparative genomic analysis of primary tumors and metastases in breast cancer. Bertucci F Oncotarget 2016 PMID: 27028851
Improving performance of multigene panels for genomic analysis of cancer predisposition. Shirts BH Genetics in medicine : official journal of the American College of Medical Genetics 2016 PMID: 26845104
Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Grant RC Gastroenterology 2015 PMID: 25479140
Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations. Kraus C International journal of cancer 2015 PMID: 25142776
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. Bodian DL PloS one 2014 PMID: 24728327
A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes. Hansen MF Molecular genetics & genomic medicine 2014 PMID: 24689082
Inactivation of DNA mismatch repair by variants of uncertain significance in the PMS2 gene. Drost M Human mutation 2013 PMID: 24027009
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
Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing. Bartley AN Cancer prevention research (Philadelphia, Pa.) 2012 PMID: 22086678
Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. Vaughn CP Human mutation 2010 PMID: 20205264
Functional PMS2 hybrid alleles containing a pseudogene-specific missense variant trace back to a single ancient intrachromosomal recombination event. Ganster C Human mutation 2010 PMID: 20186689
Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients. van der Klift HM Human mutation 2010 PMID: 20186688
Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome. Berginc G Familial cancer 2009 PMID: 19526325
Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. De Vos M American journal of human genetics 2004 PMID: 15077197
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
Mutational analysis of the PMS2 gene in sporadic endometrial cancers with microsatellite instability. Basil JB Gynecologic oncology 1999 PMID: 10479499
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMS2 - - - -

Text-mined citations for rs63750685...

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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 07, 2021