Comparison of Somatic and Germline Variant Interpretation in Hereditary Cancer Genes

Abstract

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Identification and Management of Pathogenic Variants inBRCA1,BRCA2, andPALB2in a Tumor-Only Genomic Testing Program

“…Nomenclature disparities further complicate the reporting of germline variants on tumor genomic testing reports (21). Experts in the field have developed a framework for assessing somatic results that warrant a referral for germline testing (40)(41)(42). However, many clinicians are not equipped to apply this framework in practice.…”

Discordant Reporting of a Previously Undescribed Pathogenic Germline BRCA2 Variant in Blood and Tumor Tissue in a Patient With Pancreatic Adenocarcinoma

“…In contrast, this BRCA2 variant was not reported when tumor tissue was sequenced with the commercial HRR-HRD assay. A substantial proportion of genomic variants are classified differently in the germline versus genomic tumor-profiling context, 11 and commercial panels may limit the reported tumor variants to those considered functionally relevant by their own criteria, especially when used as the screening assay for molecular-guided clinical trials. We believe that it is likely that the BRCA2 splice variant was considered nonrelevant by their classification system and thus not included in the report, with critical consequences for the treatment options in this patient case.…”

Discrepancies between tumor genomic profiling and germline genetic testing

“…5,6 Differing variant classification methods, intentional exclusion of germline variants on TGP reports, low variant allele fraction, and allelic dropout all may lead to discrepancies between PVs found by TGP and designated germline genetic testing. [7][8][9] Designated germline genetic testing laboratories use technologies optimized for the identification of germline PVs, including those that may be challenging to detect. [10][11][12] Additionally, these laboratories classify variants based on guidelines published by the American College of Medical Genetics and Genomics which differ from those guidelines utilized by TGP laboratories.…”