IN PROGRESS MLH1 Gene Curation

Gene-disease assertions not curated here (add link or write note):

Disease	Lynch syndrome
Inheritance	Autosomal dominant
Prevalence Possible sources Orphanet Medline Plus Genetics	1:279 Source: https://www.ncbi.nlm.nih.gov/books/NBK1211/
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD	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 Classifications (pts) 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 Mechanisms 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
Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID)	Moderate (age-related) Source: PMID: 20301390
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)	Adulthood Source: https://rarediseases.info.nih.gov/diseases/9905/lynch-syndrome
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.	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 https://hpo.jax.org/app/	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
Curation Summary Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited	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.
Case ID, Curator name, Date, Jira ticket link

Disease	Mismatch repair cancer syndrome 1
Inheritance	Autosomal recessive
Prevalence Possible sources Orphanet Medline Plus Genetics	Source:
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD
Clinical Validity Scoring Notes and points	Variant/Case Evidence: Segregation Evidence: Case/Control Evidence: Experimental Evidence: Source:
Clinical Validity Points Total	Source:
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Source:
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function / Gain of function / Dominant Negative
Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID)	Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
Clinical Features	Sources:
HPO Terms https://hpo.jax.org/app/
Gene SOPs & Notes	LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant
Curation Summary Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited
Case ID, Curator name, Date, Jira ticket link

IN PROGRESS MLH1 Gene Curation

Lynch syndrome

Mismatch repair cancer syndrome 1