Comparison of Somatic and Germline Variant Interpretation in Hereditary Cancer Genes

To compare the classification of genetic variants reported on tumor genomic profiling (TGP) reports with germline classifications on clinical test results and ClinVar. Results will help to inform germline testing discussions and decisions in patients with tumor variants in genes that are relevant to hereditary cancer risk.

This study compared somatic and germline classifications of small nucleotide variants in the following genes: BRCA1, BRCA2, CHEK2, PALB2, ATM, MLH1, MSH2, MSH6, and PMS2. Somatic classifications were taken from reports from a single commercial TGP laboratory of tests ordered by providers at Huntsman Cancer Institute between March 2014 and June 2018. Somatic variant interpretations were compared with classifications from germline test results as well as with ClinVar interpretations.

Of the 623 variants identified on TGP, 353 had a definitive classification in ClinVar, and 103 were assayed with a germline test, with 66 of the variants tested observed in germline. Analysis of somatic variants of uncertain significance listed on TGP reports determined that 22% had a different interpretation compared with ClinVar and that 32% differed from the interpretation on a germline test result. Pathogenic variants on TGP test results were found to differ 13% and 5% of the time compared with ClinVar interpretations and germline test results, respectively.

These results suggest that TGP variants are often classified differently in a germline context. Differences may be due to different processes in variant interpretation between somatic and germline laboratories. These results are important for health care providers to consider when making decisions about additional testing for hereditary cancer risks.