PMS2
PMS1 homolog 2, mismatch repair system component, the group of MutL homologs
Basic information
Region (hg38): 7:5970924-6009130
Previous symbols: [ "PMSL2" ]
Links
Phenotypes
GenCC
Source:
- mismatch repair cancer syndrome 1 (Definitive), mode of inheritance: AR
- rhabdomyosarcoma (Moderate), mode of inheritance: AR
- Lynch syndrome 4 (Strong), mode of inheritance: AD
- ovarian cancer (Moderate), mode of inheritance: AD
- malignant pancreatic neoplasm (Moderate), mode of inheritance: AD
- Muir-Torre syndrome (Moderate), mode of inheritance: AR
- Lynch syndrome (Supportive), mode of inheritance: AD
- mismatch repair cancer syndrome 1 (Supportive), mode of inheritance: AR
- breast cancer (Limited), mode of inheritance: AD
- prostate cancer (Limited), mode of inheritance: AD
- Lynch syndrome 4 (Definitive), mode of inheritance: AD
- mismatch repair cancer syndrome 4 (Strong), mode of inheritance: AR
- Lynch syndrome 4 (Strong), mode of inheritance: AD
- Lynch syndrome (Definitive), mode of inheritance: AD
- hereditary breast carcinoma (Disputed Evidence), mode of inheritance: AD
- mismatch repair cancer syndrome 1 (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Colorectal cancer, hereditary nonpolyposis type 4 (Lynch syndrome 4); Mismatch repair cancer syndrome 4 | AD/AR | Oncologic | For surveillance, colonoscopy with polyp removal is indicated starting at (whichever is earlier) age 20-25 years or 10 years prior to the earliest familial diagnosis; Prophylactic Hysterectomy with bilateral oophorectomy may be considered after childbearing is completed; For individuals with colon cancer, surgical treatment with full colectomy (and ileorectal anastomosis) is recommended; Cigarette smoking should be avoided; For other tumor types (individuals may be at risk of a number of cancer types), awareness of cancer risk may allow early diagnosis and treatment, which may reduce morbidity and mortality; Individuals with Mismatch repair cancer syndrome are at risk of multiple types of malignancy, and awareness may allow early detection and management | Dermatologic; Oncologic | 8072530; 7661930; 4574005; 15077197; 17557300; 19851131; 20587412; 20301390; 22461402; 22577899; 22933731; 24434690; 25856668; 29345684 |
| Individuals may be at risk for additional types of malignancy |
ClinVar
This is a list of variants' phenotypes submitted to
- Hereditary cancer-predisposing syndrome (3230 variants)
- Hereditary nonpolyposis colorectal neoplasms (3130 variants)
- not provided (956 variants)
- Lynch syndrome 4 (816 variants)
- not specified (630 variants)
- Lynch syndrome (212 variants)
- Breast and/or ovarian cancer (115 variants)
- Hereditary nonpolyposis colon cancer (58 variants)
- Malignant tumor of breast (56 variants)
- PMS2-related condition (44 variants)
- Endometrial carcinoma (37 variants)
- Lynch syndrome 1 (34 variants)
- Mismatch repair cancer syndrome 1;Lynch syndrome 4 (30 variants)
- Mismatch repair cancer syndrome 4 (25 variants)
- Lynch syndrome 4;Mismatch repair cancer syndrome 4 (23 variants)
- Carcinoma of colon (23 variants)
- Mismatch repair cancer syndrome 1 (21 variants)
- Mismatch repair cancer syndrome 4;Lynch syndrome 4 (17 variants)
- Ovarian cancer (10 variants)
- Hereditary breast ovarian cancer syndrome (10 variants)
- Gastric cancer (9 variants)
- Lynch syndrome 4;Mismatch repair cancer syndrome 1 (8 variants)
- Lynch-like syndrome (7 variants)
- Hereditary cancer (6 variants)
- Lynch syndrome;Mismatch repair cancer syndrome 4 (5 variants)
- Breast neoplasm (4 variants)
- Neoplasm of ovary (3 variants)
- Familial cancer of breast (2 variants)
- Polyp of colon (2 variants)
- Breast carcinoma (2 variants)
- Mismatch repair cancer syndrome 4;Lynch syndrome (2 variants)
- Mismatch repair cancer syndrome 1;Lynch syndrome (1 variants)
- Pituitary carcinoma (1 variants)
- Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype (1 variants)
- Rhabdomyosarcoma (1 variants)
- Hereditary nonpolyposis colorectal carcinoma (1 variants)
- Pulmonary arterial hypertension;Respiratory insufficiency;Pulmonary valve insufficiency (1 variants)
- Burkitt lymphoma;Lymphoma (1 variants)
- PMS2-related cancer disorders (1 variants)
- Colorectal cancer, non-polyposis (1 variants)
- BAP1-related tumor predisposition syndrome (1 variants)
- Lynch syndrome 5 (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the PMS2 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 756 | 773 | ||||
| missense | 19 | 2216 | 23 | 11 | 2269 | |
| nonsense | 161 | 32 | 194 | |||
| start loss | 8 | |||||
| frameshift | 340 | 62 | 410 | |||
| inframe indel | 36 | 36 | ||||
| splice donor/acceptor (+/-2bp) | 10 | 115 | 127 | |||
| splice region ? | 2 | 102 | 92 | 4 | 200 | |
| non coding ? | 45 | 284 | 27 | 357 | ||
| Total | 514 | 235 | 2317 | 1063 | 45 |
Highest pathogenic variant AF is 0.000164
Variants in PMS2
This is a list of pathogenic ClinVar variants found in the PMS2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| PMS2 | protein_coding | protein_coding | ENST00000265849 | 15 | 35887 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 4.52e-27 | 0.000279 | 125655 | 0 | 93 | 125748 | 0.000370 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | -0.557 | 502 | 468 | 1.07 | 0.0000263 | 5677 |
| Missense in Polyphen | 180 | 190.43 | 0.94524 | 2386 | ||
| Synonymous | -1.07 | 194 | 176 | 1.10 | 0.0000111 | 1619 |
| Loss of Function | 0.146 | 41 | 42.0 | 0.976 | 0.00000247 | 478 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00110 | 0.00109 |
| Ashkenazi Jewish | 0.0000992 | 0.0000992 |
| East Asian | 0.000331 | 0.000326 |
| Finnish | 0.0000925 | 0.0000924 |
| European (Non-Finnish) | 0.000409 | 0.000387 |
| Middle Eastern | 0.000331 | 0.000326 |
| South Asian | 0.000499 | 0.000490 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MLH1 to form MutL alpha. DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2- MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. {ECO:0000269|PubMed:16873062, ECO:0000269|PubMed:18206974, ECO:0000269|PubMed:23709753}.;
- Disease
- DISEASE: Hereditary non-polyposis colorectal cancer 4 (HNPCC4) [MIM:614337]: An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. {ECO:0000269|PubMed:10480359, ECO:0000269|PubMed:11793469, ECO:0000269|PubMed:15887124, ECO:0000269|PubMed:16472587, ECO:0000269|PubMed:16619239, ECO:0000269|PubMed:18178629, ECO:0000269|PubMed:18602922, ECO:0000269|PubMed:19479271, ECO:0000269|PubMed:23709753, ECO:0000269|PubMed:24027009}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: An autosomal recessive, rare, childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. Areas of skin hypopigmentation have also been reported in MMRCS patients. {ECO:0000269|PubMed:15077197, ECO:0000269|PubMed:17557300, ECO:0000269|PubMed:27435373, ECO:0000269|PubMed:7661930, ECO:0000269|PubMed:9419979}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Fanconi anemia pathway - Homo sapiens (human);Mismatch repair - Homo sapiens (human);TP53 Regulates Transcription of DNA Repair Genes;Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta);Mismatch Repair;DNA Repair;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;TP53 Regulates Transcription of DNA Repair Genes;Transcriptional Regulation by TP53;Direct p53 effectors;Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
(Consensus)
Intolerance Scores
- loftool
- 0.382
- rvis_EVS
- 1.48
- rvis_percentile_EVS
- 95.29
Haploinsufficiency Scores
- pHI
- 0.778
- hipred
- N
- hipred_score
- 0.498
- ghis
- 0.495
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.989
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Pms2
- Phenotype
- homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; digestive/alimentary phenotype; immune system phenotype; liver/biliary system phenotype; neoplasm;
Gene ontology
- Biological process
- mismatch repair;somatic hypermutation of immunoglobulin genes;response to drug;nucleic acid phosphodiester bond hydrolysis
- Cellular component
- nucleus;nucleoplasm;cytosol;plasma membrane;microtubule cytoskeleton;mismatch repair complex;MutLalpha complex;cytoplasmic ribonucleoprotein granule
- Molecular function
- DNA binding;single-stranded DNA binding;endonuclease activity;protein binding;ATP binding;ATPase activity;single base insertion or deletion binding;MutSalpha complex binding