MLH1 Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note): hereditary breast carcinoma curated as disputed by Breast/Ovarian Cancer GCEP
Disease | Lynch syndrome |
|---|---|
Inheritance | Autosomal dominant |
Prevalence | 1:279 |
Rapid or full curation? | Rapid Full |
ClinGen Hereditary Cancer GCEP, accessed 07.20.2023 | |
Clinical Validity Scoring Notes and points | Lynch syndrome [MONDO:0005835], also known as Hereditary Nonpolyposis Colon Cancer [HNPCC, MONDO:0018630], is a group of autosomal dominant cancer predisposing syndrome. 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. MLH1 has been linked to Lynch Syndrome, or HNPCC in the early 1990s (PMID: 8072530). Of note, this gene has also been implicated in autosomal recessive mismatch repair cancer syndrome 1 (MONDO:0010159), which has been assessed separately due to the difference in inheritance pattern and cancer phenotype. The MLH1 gene encodes the MLH1 protein. MLH1 protein and PMS2 protein form a heterodimer called MutLα, which is required for the DNA mismatch repair (MMR) pathway. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. Heterozygous loss of function variants in MLH1 gene have been repetitively reported in colon cancer families and individuals from various populations. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Ten loss of function variants in this gene reported in 10 probands from 10 families in 3 publications (PMIDs: 18566915, 24802709 and 33335961) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by expression, functional studies (6 points) given MLH1’s critical role in efficient mismatch repair and mouse models. (PMIDs: 24802709, 8673133 and 10096563). Mice with a Mlh1 null variant developed gastrointestinal (GI) and extra-GI tumors with microsatellite instability-high status. Mlh1-deficiency also resulted in an elevated level of CA-repeat mutation in spleen DNA. In summary, MLH1 is definitively associated with autosomal dominant Lynch syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Source: ClinGen Hereditary Cancer GCEP, accessed 07.20.2023 |
Clinical Validity Points Total | 18 Source: ClinGen Hereditary Cancer GCEP, accessed 07.20.2023 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: ClinGen Hereditary Cancer GCEP, accessed 07.20.2023 |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function Source: ClinGen Hereditary Cancer GCEP, accessed 07.20.2023. PMID: 18566915, 24802709, 33335961, 10096563
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Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) | Moderate (age-related) Source: PMID: 20301390 |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Adulthood Source: https://rarediseases.info.nih.gov/diseases/9905/lynch-syndrome |
Severity | Moderate |
Clinical Features | Increased risk for colorectal cancer and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Sources: PMID: 20301390 |
HPO Terms | HP:0006716 Hereditary nonpolyposis colorectal carcinoma HP:0010784 Uterine neoplasm HP:0100615 Ovarian neoplasm HP:0012126 Stomach cancer HP:0100833 Neoplasm of the small intestine HP:0010786Urinary tract neoplasm HP:0100574Biliary tract neoplasm HP:0012174Glioblastoma multiforme HP:0009720Adenoma sebaceum HP:0030410Sebaceous gland carcinoma HP:0031525Keratoacanthoma HP:0002894Neoplasm of the pancreas HP:0012125Prostate cancer |
Gene SOPs & Notes | INSIGHT - PILOT RULES IN PREP https://cspec.genome.network/cspec/ui/svi/doc/GN115 HGMD variants include regulatory variants in the 5' UTR / Promoter region, gross deletions and duplications/insertions, and complex rearrangments. |
Curation Summary | The MLH1 gene is associated with autosomal dominant Lynch syndrome, which is characterized by an increased risk of colorectal cancer and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate (PMID: 20301390). The National Comprehensive Cancer Network describes guidelines for the surveillance and prevention strategies for individuals at risk for Lynch syndrome due to pathogenic MLH1 variants.
The MLH1 gene is also associated with autosomal recessive mismatch repair deficiency syndrome, which is characterized by colonic adenomas, cafe au lait macules, hematologic cancers, brain tumors, cavernous brain hemangiomas, agenesis of the corpus callosum, other malignancies and congenital malformations (PMID: 24737826). |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 07.21.2023 https://broadinstitute.atlassian.net/browse/BCL-1 |
Disease | Mismatch repair cancer syndrome 1aka Constitutional mismatch repair deficiency syndrome |
|---|---|
Inheritance | Autosomal recessive |
Prevalence | Unknown Source: ORPHA:252202 |
Rapid or full curation? | Rapid Full |
ClinGen Hereditary Cancer GCEP, accessed 07.21.2023 | |
Clinical Validity Scoring Notes and points | There is sufficient evidence published associating the MLH1 gene with constitutional mismatch repair deficiency syndrome - a distinct disorder from Lynch syndrome - since the gene-disease relationship was first proposed by Wang et al., (1999). Multiple case level studies have been performed with cMMRD patients that have variants in the MLH1 gene. Other mismatch repair (MMR) genes MSH2, MSH6 and PMS2 also causes constitutional mismatch repair deficiency syndrome. Patients' tumors and normal tissue were both negative for MLH1 protein. Multiple MLH1 deficient mouse and zebrafish models have been established to show consistent phenotypes with cMMRD patients by developing neurofibromas, lymphoma, gastrointestinal carcinoma and skin tumors. This evidence is consistent with a definitive relationship between the MLH1 gene and constitutional mismatch repair deficiency syndrome. Source: ClinGen Hereditary Cancer GCEP, accessed 07.21.2023 |
Clinical Validity Points Total | 18 Source: ClinGen Hereditary Cancer GCEP, accessed 07.21.2023 |
Clinical Validity Classification | Definitive Source: ClinGen Hereditary Cancer GCEP, accessed 07.21.2023 |
Molecular Mechanism | Loss of function 2 LOF variants + mouse model
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Penetrance (list source/PMID) | Unknown
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Age of Onset (list source/PMID) | Pediatric |
Severity | Moderate - severe |
Clinical Features | Colonic adenomas, cafe au lait macules, hematologic cancers (Non-hodgkin’s lymphoma, lymphoid leukemia, AML), brain tumors (glioblastoma, medulloblastoma, supratentorial primitive neuroectodermal tumours ), cavernous brain hemangiomas, agenesis of the corpus callosum, other malignancies and congenital malformations. Sources: PMID: 24737826 |
HPO Terms | Neoplasm of the colon HP:0100273 HP:0040276Adenocarcinoma of the colon Non-Hodgkin lymphoma HP:0012539 HP:0002885Medulloblastoma HP:0001010Hypopigmentation of the skin HP:0012174Glioblastoma multiforme HP:0001274Agenesis of corpus callosum HP:0007565Multiple cafe-au-lait spots HP:0004377Hematological neoplasm |
Gene SOPs & Notes | HGMD variants include regulatory variants in the 5' UTR / Promoter region, gross deletions and duplications/insertions, and complex rearrangments. |
Curation Summary | SEE ABOVE |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 07.21.2023 https://broadinstitute.atlassian.net/browse/BCL-1 |