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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GENE SCENE SPOTLIGHT: This gene is not on the ACMG Secondary Findings List, but given the recent new data characterizing RPS20 as a colorectal cancer predisposition gene, we wanted to spotlight this one, shedding some light on the first hereditary CRC gene to be characterized since 2013.

Clinical Phenotype Summary:  

The RPS20 gene (NM_001023.3) is located on chromosome 8q12.1, encodes the small ribosomal subunit protein uS10, and contains 4 coding exons. Pathogenic variants in this gene are known to cause RPS20-related colorectal cancer (CRC) predisposition, which is inherited in an autosomal dominant fashion. RPS20-related CRC is characterized by a significantly increased risk for CRC. 

RPS20-related CRC is characterized by: 
•    A significantly increased risk for CRC

Penetrance data is currently limited, but is suggested to be high; cancer risks will differ based on individual and family history. 

Variants that lead to premature truncation have been reported as disease-causing for RPS20-related colorectal cancer predisposition. 

Unique Considerations:  
Until recently, RPS20 had limited evidence supporting its role in hereditary CRC due to its rarity. Now, we recognize it as one of the newest genes associated with AD CRC predisposition (the first to be characterized since POLE and POLD1 in 2013).

Historic data has been limited—until recently, there were only 5 families published in the literature. So far, mutations in this gene appear to be rare but significant: RPS20 loss of function variants have a CRC risk comparable to (likely) pathogenic MLH1 alterations. We’ve observed a 53-fold higher prevalence of CRC in individuals with RPS20 disease-causing variants compared to wild-type. Despite the high risks, the frequency of RPS20 disease-causing variants appears to be approximately 100-fold rarer than those causing MLH1-related Lynch syndrome. In addition, because of this rarity, the association between RPS20 loss of function and extracolonic cancers remains to be resolved.

Clinical Resources:  
Clinician Management Resource for RPS20 and Understanding Your Positive RPS20 Test Result
  
Ambry Knows Genes:  

Peer-Reviewed Publications:
•    Association of RPS20 Loss-of-Function Variants With Colorectal Cancer Risk in a Cohort of Over 950,000 Individuals (JCO Precision Oncology, Aug 2025)

Scientific Posters: 
•    Characterization of RPS20-related colorectal cancer predisposition: A case series from a multigene panel testing cohort (ACMG 2025, Top 25 Posters Designation)

Citations:  
•    Nieminen TT, et al. (2014) Gastroenterology 147(3):595-598.e5 PMID: 24941021 
•    Broderick P, et al. (2017) Gastroenterology 152(1):75-77.e4 PMID: 27713038
•    Thompson BA, et al. (2020) Clin Genet 97(6):943-944 PMID: 32424863
•    Djursby M, et al. (2020) Front Genet 11(0):566266 PMID: 33193653
•    Herrera-Mullar J, et al. (2025) Gen in Med Open 3:2 [abstract]

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.