Impact of a Cancer Gene Variant Reclassification Program Over a 20-Year Period

Abstract

PURPOSE Hereditary cancer genetic testing can inform personalized medical management for individuals at increased cancer risk. However, many variants in cancer predisposition genes are individually rare, and traditional tools may be insufficient to evaluate pathogenicity. This analysis presents data on variant classification and reclassification over a 20-year period. PATIENTS AND METHODS This is a retrospective analysis of > 1.9 million individuals who received hereditary cancer genetic testing from a single clinical laboratory (March 1997 to December 2017). Variant classification included review of evidence from traditional tools (eg, population frequency databases, literature) and laboratory-developed tools (eg, novel statistical methods, in-house RNA analysis) by a multidisciplinary expert committee. Variants may have been reclassified more than once and with more than one line of evidence. RESULTS In this time period, 62,842 unique variants were observed across 25 cancer predisposition genes, and 2,976 variants were reclassified. Overall, 82.1% of reclassification events were downgrades (eg, variant of uncertain significance [VUS] to benign), and 17.9% were upgrades (eg, VUS to pathogenic). Among reclassified variants, 82.8% were initially classified as VUS, and 47.5% were identified in ≤ 20 individuals (allele frequency ≤ 0.001%). Laboratory-developed tools were used in 72.3% of variant reclassification events, which affected > 600,000 individuals. More than 1.3 million patients were identified as carrying a variant that was reclassified within this 20-year time period. CONCLUSION The variant classification program used by the laboratory evaluated here enabled the reclassification of variants that were individually rare. Laboratory-developed tools were a key component of this program and were used in the majority of reclassifications. This demonstrates the importance of using robust and novel tools to reclassify rare variants to appropriately inform personalized medical management.

Clinical Utility of Functional RNA Analysis for the Reclassification of Splicing Gene Variants in Hereditary Cancer

“…VUS reclassification efforts have shown that 97.2% of VUS can be reclassified in the future and the majority of variants in this class (82.1%) are likely benign (14). In our study, RNA analysis contributed to the reclassification of 20% of splicing VUS to pathogenic.…”

Splicing in the Diagnosis of Rare Disease: Advances and Challenges

“…Care must be taken in the interpretation of splicing variants, even where functional assessment is conducted. Numerous examples of conflicting variant interpretations and changes in interpretation over time exist in the literature, and splicing variants appear to be enriched for these reclassifications relative to many other variant types ( Esterling et al, 2020 ). This has been particularly well documented in familial cancer syndromes associated with BRCA1 and BRCA2 variants, where pathogenic variants are clinically actionable.…”

Economic impact of multigene panel testing for hereditary breast and ovarian cancer

“…The panel test identified an elevated risk for eight hereditary cancers (breast, ovarian, colorectal, endometrial, melanoma, pancreatic, gastric and prostate) due to variants in the following genes: BRCA1, BRCA2, ATM, CDH1, CHEK2, NBN, PALB2, PTEN, STK11, TP53, BRIP1, RAD51C, RAD51D, MSH2, MLH1, MSH6, PMS2, EPCAM, APC, BARD1, BMPR1A, CDK4, CDKN2A, MUTYH and SMAD4. Variant classification was based on joint guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [27], as previously described [28,29]. Patients were assigned to groups based on the test received (panel or SS) and test result: positive (identification of ≥1 pathogenic variant [laboratory classification of deleterious or suspected deleterious] or a variant with a special interpretation finding noting possible increased cancer risks), VUS (identification of ≥1 variant without sufficient evidence of increased cancer risk and no pathogenic variants), negative (no identification of pathogenic variants or VUS).…”