IN PROGRESS MSH6 Gene Curation

Gene-disease assertions not curated here (add link or write note): hereditary breast carcinoma (disputed by hereditary cancer GCEP).

Disease	Lynch syndrome
Inheritance	Autosomal dominant
Prevalence Possible sources Orphanet Medline Plus Genetics	1:279 Source: 20301390
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD	ClinGen Hereditary Cancer GCEP, accessed 08.04.2023
Clinical Validity Scoring Notes and points	MSH6 was first reported in relation to autosomal dominant Lynch Syndrome (LS, MONDO:0005835) in 1997 (Miyaki M. et al., PMID: 9354786). Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer (HNPCC), is a cancer predisposition syndrome; LS is caused by pathogenic germline variants (PGV) in DNA mismatch repair (MMR) genes, including MSH6, inherited in an autosomal dominant pattern. Biallelic MSH6 PGVs also cause a distinct mismatch repair deficiency cancer syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we separate these two curations due to different inheritance patterns and phenotype. This curation only focuses on the dominant LS condition. In this curation, we included 14 PGVs, including missense, deletions, nonsense, and duplications that have been reported in multiple patients and families (PMIDs: 9354786, 10521294, 36612224, 11709755, 26805314). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function (LOF). MSH6-Lynch Syndrome association is supported by experimental evidence at a biochemical and functional level (6 points). Drummond JT et al., 1995, (PMID: 7604264) describes the isolation of an MSH2–MSH6 heterodimer that restores DNA mismatch repair to tumor cells; in the same issue, Palombo F, et al., 1995, (PMID: 7604265) reported that the DNA mismatch recognition and binding in human cells has been thought to be mediated by the hMSH2 protein, they showed that the mismatch-binding factor consists of two distinct proteins, the 100-kilodalton hMSH2 and a 160-kilodalton polypeptide, GTBP (for G/T binding protein). Both proteins are required for mismatch-specific binding, a result consistent with the finding that tumor-derived cell lines devoid of either protein are also devoid of mismatch-binding activity. Sequence analysis identified GTBP as a new member of the MutS homolog family. Edelmann W, et al., (PMID: 9390556) also reported that extracts from the Msh6-/- cells were defective for the repair of single nucleotide mismatches. In addition, homozygous mice had a reduced lifespan and developed a spectrum of tumors. The mice showed tumors in the intestine (adenoma), the liver (hepatoma), and B- and T-cell lymphomas. In summary, MSH6 is definitively associated with autosomal dominant inheritance and Lynch Syndrome. This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This gene-disease pair was initially evaluated by the Colon Cancer Expert Panel on 09/25/2017. It was reevaluated on 03/24/2023 (SOP Version 9). As a result of this reevaluation, the classification did not change. Source: ClinGen Hereditary Cancer GCEP, accessed 08.04.2023
Clinical Validity Points Total	18 Source: ClinGen Hereditary Cancer GCEP, accessed 08.04.2023
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 08.04.2023
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function Source: ClinGen Hereditary Cancer GCEP, accessed 08.04.2023. pLOF variants used in curation: NM_000179.3(MSH6):c.3772C>T (p.Gln1258Ter) 10521294 NM_000179.3(MSH6):c.651dup (p.Lys218Ter) 10521294 NM_000179.3(MSH6):c.3838C>T (p.Gln1280Ter) 11709755
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	None found
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 MSH6 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 MSH6 variants. The MSH6 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 08.04.2023, BCL-1 - Getting issue details... STATUS

Disease	Mismatch repair cancer syndrome aka Constitutional mismatch repair deficiency syndrome
Inheritance	Autosomal recessive
Prevalence Possible sources Orphanet Medline Plus Genetics	Unknown Source: ORPHA:252202
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD	ClinGen Hereditary Cancer GCEP, accessed 08.04.2023
Clinical Validity Scoring Notes and points	There has been sufficient evidence published associating the MSH6 gene with constitutional mismatch repair deficiency syndrome - a distinct disorder from Lynch syndrome - since the gene-disease relationship was first proposed by Menko, et al., (2004). Multiple case level studies have been performed with cMMRD patients that have variants in the MSH6 gene. Other mismatch repair (MMR) genes MLH1, MSH2 and PMS2 also causes constitutional mismatch repair deficiency syndrome. IHC and western blot revealed absence of MSH6 protein in patient cells. Multiple MSH6 deficient mouse and zebrafish models have been established to show consistent phenotypes with MMRCS patients by developing neurofibromas, non-Hodgkin’s lymphoma (NHL) and gastrointestinal (GI) tumors. All of these types of evidence are consistent with a definitive relationship between the MSH6 gene and constitutional mismatch repair deficiency syndrome. Source: ClinGen Hereditary Cancer GCEP, accessed 08.04.2023
Clinical Validity Points Total	18 Source: ClinGen Hereditary Cancer GCEP, accessed 08.04.2023
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 08.04.2023
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function pLOF variants used in ClinGen Hereditary Cancer GCEP curation: NM_000179.3(MSH6):c.3633dup p.(Val1212Cysfs3) PMID: 16000562 NM_000179.2(MSH6):c.642C>G (p.Tyr214Ter) PMID: 17259933 NM_000179.2(MSH6):c.1806_1809delAAAG p.(Glu604Leufs5) PMID: 18409202
Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID)	Unknown Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)	Pediatric
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.	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 https://hpo.jax.org/app/	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	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	SEE ABOVE
Case ID, Curator name, Date, Jira ticket link	Andrea Oza 08.04.2023, BCL-1 - Getting issue details... STATUS

IN PROGRESS MSH6 Gene Curation

Lynch syndrome

Mismatch repair cancer syndrome