This variant is associated with the following publications: (PMID: 27616075, 24728327, 28874130, 31433215, 31332305)
NM_000535.7(PMS2):c.1437C>G (p.His479Gln)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(15); Likely benign(4)
Uncertain significance(1); Benign(15); Likely benign(4)
20 out of 28 submissions contributed to this classification
Help
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.
28
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000535.7(PMS2):c.1437C>G (p.His479Gln)
Variation ID: 41701 Accession: VCV000041701.94
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p22.1 7: 5987328 (GRCh38) [ NCBI UCSC ] 7: 6026959 (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 Mar 7, 2026 Feb 4, 2026 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000535.7:c.1437C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000526.2:p.His479Gln missense NM_001322003.2:c.1032C>G NP_001308932.1:p.His344Gln missense NM_001322004.2:c.1032C>G NP_001308933.1:p.His344Gln missense NM_001322005.2:c.1032C>G NP_001308934.1:p.His344Gln missense NM_001322006.2:c.1281C>G NP_001308935.1:p.His427Gln missense NM_001322007.2:c.1119C>G NP_001308936.1:p.His373Gln missense NM_001322008.2:c.1119C>G NP_001308937.1:p.His373Gln missense NM_001322009.2:c.1032C>G NP_001308938.1:p.His344Gln missense NM_001322010.2:c.876C>G NP_001308939.1:p.His292Gln missense NM_001322011.2:c.504C>G NP_001308940.1:p.His168Gln missense NM_001322012.2:c.504C>G NP_001308941.1:p.His168Gln missense NM_001322013.2:c.864C>G NP_001308942.1:p.His288Gln missense NM_001322014.2:c.1437C>G NP_001308943.1:p.His479Gln missense NM_001322015.2:c.1128C>G NP_001308944.1:p.His376Gln missense NR_136154.1:n.1524C>G non-coding transcript variant NC_000007.14:g.5987328G>C NC_000007.13:g.6026959G>C NG_008466.1:g.26779C>G LRG_161:g.26779C>G LRG_161t1:c.1437C>G P54278:p.His479Gln - Protein change
- H479Q, H292Q, H373Q, H427Q, H168Q, H288Q, H344Q, H376Q
- Other names
-
p.H479Q:CAC>CAG
- Canonical SPDI
- NC_000007.14:5987327:G:C
-
Global minor allele
frequency (GMAF) HelpThe 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 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00359
Trans-Omics for Precision Medicine (TOPMed) 0.00440
1000 Genomes Project 0.00280
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00515
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
6049 | 6156 | |
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. |
|---|---|---|---|---|
| Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2025 | RCV000034615.62 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 20, 2015 | RCV000076809.22 | |
| Benign/Likely benign (8) |
criteria provided, multiple submitters, no conflicts
|
Jun 19, 2025 | RCV000121844.29 | |
| Benign (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 13, 2025 | RCV000162366.16 | |
| Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2025 | RCV000625386.20 | |
| Benign (1) |
criteria provided, single submitter
|
Feb 4, 2026 | RCV001081746.18 | |
| Benign (1) |
no assertion criteria provided
|
- | RCV001356193.10 | |
| Benign (1) |
criteria provided, single submitter
|
Jun 8, 2021 | RCV003149610.9 | |
| Benign (1) |
criteria provided, single submitter
|
Jan 1, 2022 | RCV003153324.9 |
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. |
Expand all rows
Collapse all rows
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
(Dec 06, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000171026.5
First in ClinVar: Jun 09, 2014 Last updated: Oct 02, 2016 |
Comment:
show
This variant is associated with the following publications: (PMID: 27616075, 24728327, 28874130, 31433215, 31332305) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(Jun 08, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Breast and/or ovarian cancer |
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003837734.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Apr 09, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000212673.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550719.5
First in ClinVar: Jul 30, 2022 Last updated: Mar 11, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Dec 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000693232.40
First in ClinVar: May 29, 2016 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 63
|
|
|
Uncertain significance
(Nov 20, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary nonpolyposis colon cancer |
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266215.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
colon cancer (present) , other cancer (present)
Age: 50-59 years
|
|
|
Benign
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
NOT SPECIFIED |
PreventionGenetics, part of Exact Sciences
Accession: SCV000304718.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Aug 09, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697296.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
show
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 by a functional study that showed through an in vitro MMR assay that the H479Q mutant protein has significantly higher relative repair efficiency than repair-deficient control E705K (70 vs 10%, p<0.01) (Drost_2013). This variant was found in 1284/277610 control chromosomes (8 homozygotes) at a frequency of 0.0046252, which is approximately 41 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in patients where it was often reported as a benign polymorphism. However, the frequency in ExAC and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between PMS2 and its overlapping pseudogenes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Also, in multiple internal LCA samples this variant was found to co-occur with other pathogenic variants: MSH2, c.942+3A>T, BRCA1, c.68_69delAG (p.Glu23fsX17), and BRCA2, c.5946delT (p.Ser1982fsX22). One study reports the variant in a sample that was IHC-negative for MLH1 and PMS2 and with observed MLH1 hypermethylation (van der Klift_2016). Taken together, this variant is classified as benign. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Apr 14, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4 |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745193.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely benign
(May 28, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4 |
Mendelics
Accession: SCV001137298.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Likely benign
(Mar 13, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4 |
Illumina Laboratory Services, Illumina
Accession: SCV001322473.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Aug 18, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Sema4, Sema4
Accession: SCV002529794.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Feb 19, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000691015.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Benign
(Jan 01, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Ovarian cancer |
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University
Accession: SCV003843502.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(Mar 16, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Eurofins Ntd Llc (ga)
Accession: SCV000860370.2
First in ClinVar: Oct 02, 2016 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Benign
(Jan 30, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 4 |
Myriad Genetics, Inc.
Accession: SCV006094137.1
First in ClinVar: Jun 22, 2025 Last updated: Jun 22, 2025 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Benign
(Jul 13, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Laboratorio de I+D, Fundación Centro Médico de Asturias
Additional submitter:
SpadaHC, Centro de Investigación Biomédica en Red Cáncer (CIBERONC)
Accession: SCV006550696.1
First in ClinVar: Oct 05, 2025 Last updated: Oct 05, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Jun 19, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not specified |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV007304175.1
First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 15
|
|
|
Benign
(May 20, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885989.8
First in ClinVar: Feb 17, 2019 Last updated: Jan 24, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Feb 04, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary nonpolyposis colorectal neoplasms |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166374.15
First in ClinVar: Jun 23, 2014 Last updated: Mar 07, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Benign
(Nov 08, 2015)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Lynch syndrome 4 |
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745844.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Malignant tumor of breast |
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551294.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
show
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 2012, Basil 1999, Wang 1999, Berginc 2009). The variant was also identified in the following databases: dbSNP (ID: rs63750685) as “With Likely benign, Uncertain significance allele”, ClinVar (5x, as benign by GeneDx, Invitae, Ambry Genetics, Prevention Genetics, NIH, 2x, uncertain significance by InSight, University of Washington, 1x, with no classification by ITMI), Clinvitae (3x, as benign, 1x, as uncertain significance by ClinVar), Insight Colon Cancer Gene Variant Database (5x, as class 3), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (6x, as class 3). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1281 of 277210 (8 homozygous) chromosomes at a frequency of 0.004621 in the following populations: African in 237 of 24026 chromosomes (freq. 0.010), other in 31 of 6466 chromosomes (freq. 0.005), Latino in 49 of 34420 chromosomes (freq. 0.0014), European in 488 of 126712 (4 homozygous) chromosomes (freq. 0.004), Ashkenazi Jewish in 76 of 10150 chromosomes (freq. 0.007), East Asian in 16 of 18866 chromosomes (freq. 0.0008), Finnish in 290 of 25794 chromosomes (freq. 0.011), and South Asian in 94 of 30776 (3 homozygous) chromosomes (freq. 0.003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic CHEK2 variant (c.1283C>T, p.Ser428Phe) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.His479Gln variant does not have clinical significance. The p.His479Gln residue is not conserved in mammals and the variant amino acid Glutamine (Gln) is present in Chimpanzees, increasing the likelihood that this variant does not have clinical significance, 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Likely benign
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798176.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not specified |
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 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not specified |
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920582.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not specified |
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: SCV001955499.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(Jul 13, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043429.2 First in ClinVar: Apr 12, 2013 Last updated: Jun 08, 2025 |
Observation 1
Collection method: research
Allele origin: germline
Affected status: no
Number of individuals with the variant: 6
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)
Platform type: High-Throughput DNA Sequencing
Platform name: Illumina GAIIx
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not provided
(Sep 19, 2013)
N
Not contributing to aggregate classification
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no classification provided
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AllHighlyPenetrant |
ITMI
Accession: SCV000086043.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation:
7
Observation 1
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: Whole_cohort
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 2
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: African
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 3
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: African_European
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 4
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: Central_Asian
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 5
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: East_Asian
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 6
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: European
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 7
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: Hispanic
Platform Type: next-gen sequencing
Platform Name: Complete Genomics
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Comment:
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:
PMS2: BP4, BS2
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 by a functional study that showed through an in vitro MMR assay that the H479Q mutant protein has significantly higher relative repair efficiency than repair-deficient control E705K (70 vs 10%, p<0.01) (Drost_2013). This variant was found in 1284/277610 control chromosomes (8 homozygotes) at a frequency of 0.0046252, which is approximately 41 times the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in patients where it was often reported as a benign polymorphism. However, the frequency in ExAC and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between PMS2 and its overlapping pseudogenes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Also, in multiple internal LCA samples this variant was found to co-occur with other pathogenic variants: MSH2, c.942+3A>T, BRCA1, c.68_69delAG (p.Glu23fsX17), and BRCA2, c.5946delT (p.Ser1982fsX22). One study reports the variant in a sample that was IHC-negative for MLH1 and PMS2 and with observed MLH1 hypermethylation (van der Klift_2016). Taken together, this variant is classified as benign.
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 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.
Comment:
BS1+BS2+BP4_Strong+BP1_Supporting
Comment:
BA1, BP4_moderate
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 2012, Basil 1999, Wang 1999, Berginc 2009). The variant was also identified in the following databases: dbSNP (ID: rs63750685) as “With Likely benign, Uncertain significance allele”, ClinVar (5x, as benign by GeneDx, Invitae, Ambry Genetics, Prevention Genetics, NIH, 2x, uncertain significance by InSight, University of Washington, 1x, with no classification by ITMI), Clinvitae (3x, as benign, 1x, as uncertain significance by ClinVar), Insight Colon Cancer Gene Variant Database (5x, as class 3), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (6x, as class 3). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1281 of 277210 (8 homozygous) chromosomes at a frequency of 0.004621 in the following populations: African in 237 of 24026 chromosomes (freq. 0.010), other in 31 of 6466 chromosomes (freq. 0.005), Latino in 49 of 34420 chromosomes (freq. 0.0014), European in 488 of 126712 (4 homozygous) chromosomes (freq. 0.004), Ashkenazi Jewish in 76 of 10150 chromosomes (freq. 0.007), East Asian in 16 of 18866 chromosomes (freq. 0.0008), Finnish in 290 of 25794 chromosomes (freq. 0.011), and South Asian in 94 of 30776 (3 homozygous) chromosomes (freq. 0.003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic CHEK2 variant (c.1283C>T, p.Ser428Phe) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.His479Gln variant does not have clinical significance. The p.His479Gln residue is not conserved in mammals and the variant amino acid Glutamine (Gln) is present in Chimpanzees, increasing the likelihood that this variant does not have clinical significance, 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Comment:
Converted during submission from no known pathogenicity to Benign.
Citations for germline classification of this variant
Help| 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 |
| 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 |
| 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 |
| 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 | - | - | - | - |
| https://spadahc.ciberisciii.es/variant/GRCH37/7%206026959%20G/C | - | - | - | - |
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Text-mined citations for rs63750685 ...
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Record last updated Mar 08, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.