MSH2 Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note): Breast cancer (refuted by Hereditary cancer GCEP)
Disease | Lynch syndrome |
|---|---|
Inheritance | Autosomal autosomal dominant |
Prevalence | 1:279 Source: PMID: 20301390 |
Rapid or full curation? | Rapid Full |
Hereditary Cancer GCEP, accessed 07.21.2023 | |
Clinical Validity Scoring Notes and points | Lynch syndrome [MONDO:0005835], also known as Hereditary Nonpolyposis Colon Cancer [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. MSH2 has been linked to Lynch Syndrome, or HNPCC in the early 1990s (PMID: 8261515 and 8252616). Of note, this gene has also been implicated in autosomal recessive mismatch repair cancer syndrome 1 (MONDO:0010159), which has been assessed separately. MSH2 gene encodes MSH2 protein, which heterodimerizes with MSH6 or MSH3 to form MSH2-MSH6 or MSH2-MSH3 complex (also named MutSα and MutSβ, respectively). Both MutSα and MutSβ are 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. Loss of function variants in MSH2 gene have been repetitively reported in families and individuals from various populations. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Eight loss of function variants in this gene reported in 9 probands from 9 families in 2 publications (PMID:18566915, 32161499) is 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) demonstrating MSH2’s role in mismatch repair and mouse models (PMIDs: 19324997, 7550317, 7628020). Homozygous Msh2-/- mice began, with high frequency, to develop lymphoid tumors containing microsatellite instabilities at an early age. In addition, Msh2-deficient mouse ES cells lost mismatch binding and acquired microsatellite instability. In summary, MSH2 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: Hereditary Cancer GCEP, accessed 07.21.2023 |
Clinical Validity Points Total | 18 Source: Hereditary Cancer GCEP, accessed 07.21.2023 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: Hereditary Cancer GCEP, accessed 07.21.2023 |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function Source: Hereditary Cancer GCEP, accessed 07.21.2023. PMID: 18566915, 32161499. |
Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) | Moderate Source: PMID: 20301390 |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Adulthood |
Severity | Moderate |
Clinical Features | Increased risk of cancers, including colorectal, endometrial, ovarian, stomach/small bowel, ureter/kidney, bladder, prostate, brain, breast Source: PMID: 20301390 |
HPO Terms | HP:0003003 Colon cancer HP:0006725 Pancreatic adenocarcinoma HP:0200008 Intestinal polyposis HP:0012114 Endometrial carcinoma HP:0012125 Prostate cancer HP:0002862 Bladder carcinoma |
Gene SOPs & Notes | Exon 1 PTCs - Rescue Effect |
Curation Summary | The MSH2 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 MSH2 variants.
The MSH2 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, https://broadinstitute.atlassian.net/browse/BCL-1 |
Disease | Mismatch Repair Cancer Syndrome |
|---|---|
Inheritance | Autosomal recessive / autosomal dominant / X-linked |
Prevalence | Unknown, rare. More than 200. individuals reported in literature Source: Medline Plus Genetics |
Rapid or full curation? | Rapid Full |
ClinGen Hereditary Cancer GCEP, accessed 08.04.2023 | |
Clinical Validity Scoring Notes and points | There has been sufficient amount of evidence published associating the MSH2 gene with constitutional mismatch repair deficiency syndrome - a distinct disorder from the dominant Lynch syndrome - since the gene-disease relationship was first proposed by Whiteside D, et al., (2002). Multiple case level studies have been performed with cMMRD syndrome patients that have variants in the MSH2 gene. Other mismatch repair (MMR) genes MLH1, MSH6 and PMS2 also causes constitutional mismatch repair deficiency syndrome. RNA and Immunoblotting demonstrate a lack of MSH2 protein in patient cells. Multiple MSH2 deficient mouse and zebrafish models have been established to show consistent phenotypes with cMMRD patients by developing neurofibromas and lymphoid tumors. There is sufficient evidence consistent with a definitive relationship between the MSH2 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 | Definitive Source: ClinGen Hereditary Cancer GCEP, accessed 08.04.2023 |
Molecular Mechanism | Loss of function 4 pLOF variants from ClinGen Hereditary Cancer GCEP curation:
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Penetrance (list source/PMID) | Unknown Source: |
Age of Onset (list source/PMID) | Childhood Source: https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC1055 |
Severity | Severe: Source: https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC1055 |
Clinical Features | Skin: Cafe-au-lait spots, hypopigmentation, axillary freckles Brain tumors Lymphoma Leukemia Colon cancer - adenocarcinoma GI polyposis. Sources: PMID: 24440087 https://drive.google.com/open?id=16lcl-iXynptapMZsKLIVxevjSqPAW6X_&usp=drive_fs |
HPO Terms | Multiple cafe-au-lait spots HP:0007565 Brain neoplasm HP:0030692 Lymphoma HP:0002665 Leukemia HP:0001909 Colon cancer HP:0003003 Intestinal polyposis HP:0200008 |
Gene SOPs & Notes | SEE ABOVE |
Curation Summary | see above |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, 08.04.2023, https://broadinstitute.atlassian.net/browse/BCL-1 |