Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing

Abstract

IMPORTANCE Variant reclassification is an important component of hereditary cancer genetic testing; however, there are few published data quantifying the prevalence of reclassification. OBJECTIVE Retrospective cohort study of individuals who had genetic testing from 2006 through 2016 at a single commercial laboratory. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort of individuals who had genetic testing between 2006 and 2016 at a single commercial laboratory was assessed. Variants were classified as benign, likely benign, variant of uncertain significance, likely pathogenic, or pathogenic. Retrospective chart reviews were conducted for patients from the University of Texas Southwestern (UTSW) Medical Center. EXPOSURES Hereditary cancer genetic testing. MAIN OUTCOMES AND MEASURES Frequency of and time to amended reports; frequency and types of variant reclassification. RESULTS From 2006 through 2018, 1.45 million individuals (median [interquartile range] age at testing, 49 years [40.69-58.31 years], 95.6% women) had genetic testing, and 56.6% (n = 821 724) had a personal history of cancer. A total of 1.67 million initial tests were reported and 59 955 amended reports were issued due to variant reclassification. Overall, 6.4% (2868 of 44 777) of unique variants were reclassified. Reclassification to a different clinical category was rare among unique variants initially classified as pathogenic or likely pathogenic (0.7%, 61 of 9112) or benign or likely benign (0.2%, 15 of 8995). However, 7.7% (2048 of 26 670) of unique variants of uncertain significance were reclassified: 91.2% (1867 of 2048) were downgraded to benign or likely benign (median time to amended report, 1.17 years), 8.7% (178 of 2048) were upgraded to pathogenic or likely pathogenic variants (median time to amended report, 1.86 years). Because most variants were observed in more than 1 individual, 24.9% (46 890 of 184 327) of all reported variants of uncertain significance were reclassified. CONCLUSIONS AND RELEVANCE Following hereditary cancer genetic testing at a single commercial laboratory, 24.9% of variants of uncertain significance were reclassified, which included both downgrades and upgrades. Further research is needed to assess generalizability of the findings for other laboratories, as well as the clinical consequences of the reclassification as a component of a genetic testing program.

Pilot study of EVIDENCE: High diagnostic yield and clinical utility of whole exome sequencing using an automated interpretation system for patients with suspected genetic disorders

“…Updated information on variants in genome databases can result in VUSs being classified as pathogenic or benign. 12,23,24 Before family testing and clinical reassessment, 28.8% of the patients in our study had variants classified as pathogenic or likely pathogenic; after family testing and reassessment, however, 37.6% of our patients had these variants. Following segregation analysis and clinical reassessment, 37 (41.6%) of 89 VUSs were reclassified as pathogenic or likely pathogenic.…”

How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies

“…For example, in case 4, some variants may remain as VUS until additional functional or familial segregation data become available for reclassification. 47,48 Third, definitive annotation of variants by one institution will likely remain challenging. However, consistent application of MM-VCEP rules with ClinVar data deposition and thus inter-laboratory correspondence can significantly improve the accuracy and consistency of variant curation.…”

“…ClinVar variant classifications such as VUS or those with conflicting interpretations may thus evolve to more diagnostic certainty. 47,48 Example 4. Synonymous/intronic/non-coding variants, c.508+3delA (PATH with PS3, PP1_strong, PM2, PP3, PS4_supporting), p.Thr148= (LBEN with BP4, BP7)…”

Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

“…In a diagnostic and rapid‐turnover setting, diagnostic laboratories may need to focus on testing the most clinically useful genes. In addition, large comprehensive panels lead to a higher rate of VUS and require continuous research‐based efforts in reclassification . A balance of diagnostic and research goals are encouraged in order to progress in this field.…”

“…In addition, large comprehensive panels lead to a higher rate of VUS and require continuous research-based efforts in reclassification. [44][45][46] A balance of diagnostic and research goals are encouraged in order to progress in this field.…”