Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

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Clinical Phenotype Summary: 

The MSH2 gene (NM_000251.1) is located on chromosome 2p21, encodes the DNA mismatch repair protein Msh2, and contains 16 coding exons. Pathogenic variants in this gene are known to cause Lynch syndrome (previously known as hereditary non-polyposis colorectal cancer or HNPCC), which is inherited in an autosomal dominant fashion, and constitutional mismatch repair deficiency (CMMR-D) syndrome, which is inherited in an autosomal recessive fashion. 

MSH2-related Lynch syndrome is characterized by an increased risk for the following cancers: 

• Colon cancer (33-52% cumulative lifetime risk)
• Endometrial cancer (21-57% cumulative lifetime risk in females)
• Gastric cancer (0.2-9% cumulative lifetime risk)
• Ovarian cancer (8-38% cumulative lifetime risk in females)
• Elevated risks for cancers of the:
  o  Kidney/bladder (urothelial)
  o  Pancreas
  o  Biliary tract  
  o  Sebaceous glands (a variant of Lynch syndrome also known as Muir Torre syndrome)  
  o  Central nervous system (may be elevated compared to the general population)
• Some studies have estimated that mutations in mismatch repair (MMR) genes, primarily MSH2, may be related to an approximately 2-fold increase in prostate cancer risk
• Penetrance in Lynch syndrome due to MSH2 pathogenic variants is incomplete, and variable expressivity is observed; therefore, specific cancer risks will differ based on individual and family history

Loss of function is reported as the mechanism of disease for Lynch syndrome.

CMMR-D is characterized by:

• Cafe au lait macules
• Increased risk for:
  o    Hematologic malignancies
  o    Brain tumors
  o    Early-onset Lynch syndrome-associated cancers

Biallelic loss of function has been reported as the mechanism of disease for CMMR-D.     

Unique Considerations: 

Individuals of reproductive age are at 25% risk of having a child with CMMR-D with each pregnancy when both biological partners have a pathogenic variant in MSH2. 

Clinical Resources: 
Clinician Management Resource and Understanding Your Result

Ambry Knows Genes: 
Peer-Reviewed Publications:
•    RNA sequencing uncovers clinically actionable germline intronic MSH2 variants in previously unresolved Lynch syndrome families (Apr 2022)
•    Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes (Feb 2020)
•    Rare Germline Pathogenic Mutations of DNA Repair Genes are Most Strongly Asssociated with Grade Group 5 Prostate Cancer (Feb 2020)
•    Comparison of Somatic and Germline Variant Interpretation in Hereditary Cancer Genes (Oct 2019)
•    Tumour characteristics provide evidence for germline mismatch repair variant pathogenicity (Aug 2019)
•    RNA Genetic Testing Identifies Germline Pathogenic MSH2 Tandem Duplications in Lynch Syndrome Patients (Feb 2019)

Scientific Posters:
•    MSH2 variant causing atypical CMMRD and atypical LS (CGA-GC 2024)
•    Identification of an Alu insertion in MSH2 by next-generation sequencing in a family with Lynch syndrome: An 8-year diagnostic odyssey (CGA-IGC 2020)
•    MSH2 inversion phenotype is similar to other MSH2 mutations (CGA-IGC 2015)

There's more!! To read more about Ambry’s research on this gene, visit the "Our Research" on our website https://www.ambrygen.com/science.  

Citations: 
•    Aronson M et al. J Med Genet. 2022 Apr;59(4):318-327 PMID: 33622763  
•    Bonadona V et al. JAMA, 2011 Jun;305:2304-10 PMID: 21642682
•    Dominguez-Valentin M et al. Genet Med, 2020 01;22:15-25 PMID: 31337882   
•    Dowty J et al. Hum Mutat. 2013 Mar;34(3):490-7 PMID: 23255516
•    Engel C et al. J Clin Oncol, 2012 Dec;30:4409-15 PMID: 23091106
•    Møller P et al. Gut, 2018 07;67:1306-1316 PMID: 28754778  
•    Møller P et al. Gut, 2017 03;66:464-472 PMID: 26657901 
•    Ryan S et al. Cancer Epidemiol. Biomarkers Prev. 2014 Mar;23(3):437-49 PMID: 24425144  
•    Wang C et al. JNCI Cancer Spectr. 2020 Apr 23;4(5):pkaa027 PMID: 32923933

Ambry Genetics Gene-Disease Validity Scheme   

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. 

To learn more about the ACMG Secondary Findings list, click here. 

To read all previous Gene Scene emails, click here.