Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework.

Seifert BA1, McGlaughon JL1, Jackson SA2, Ritter DI3, Roberts ME2, Schmidt RJ4, Thompson BA5, Jimenez S1, Trapp M1, Lee K1, Plon SE3, Offit K6, Stadler ZK6, Zhang L6, Greenblatt MS7, Ferber MJ8.

Author information

Abstract

PURPOSE:

Gene-disease associations implicated in hereditary colorectal cancer and polyposis susceptibility were evaluated using the ClinGen Clinical Validity framework.

METHODS:

Forty-two gene-disease pairs were assessed for strength of evidence supporting an association with hereditary colorectal cancer and/or polyposis. Genetic and experimental evidence supporting each gene-disease relationship was curated independently by two trained biocurators. Evidence was reviewed with experts and assigned a final clinical validity classification.

RESULTS:

Of all gene-disease pairs evaluated, 14/42 (33.3%) were Definitive, 1/42 (2.4%) were Strong, 6/42 (14.3%) were Moderate, 18/42 (42.9%) were Limited, and 3/42 (7.1%) were either No Reported Evidence, Disputed, or Refuted. Of panels in the National Institutes of Health Genetic Testing Registry, 4/26 (~15.4%) contain genes with Limited clinical evidence.

CONCLUSION:

Clinicians and laboratory diagnosticians should note that <60% of the genes on clinically available panels have Strong or Definitive evidence of association with hereditary colon cancer or polyposis, and >40% have only Moderate, Limited, Disputed, or Refuted evidence. Continuing to expand the structured assessment of the clinical relevance of genes listed on hereditary cancer testing panels will help clinicians and diagnostic laboratories focus the communication of genetic testing results on clinically significant genes.