Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing

Jacqueline Mersch; Nichole Brown; Sara Pirzadeh-Miller; Erin Mundt; Hannah C Cox; Krystal Brown; Melissa Aston; Lisa Esterling; Susan Manley; Theodora Ross

doi:10.1001/jama.2018.13152

Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing

Mersch J, Brown N, Pirzadeh-Miller S, Mundt E, Cox HC, Brown K, Aston M, Esterling L, Manley S, Ross T

Published September 25, 2018 JAMA

DOI 10.1001/jama.2018.13152 PMID 30264118 PMC PMC6233618

RRM Academy Synopsis

One lab reclassified 24.9% of uncertain hereditary cancer variants

One commercial laboratory reclassified 24.9% of the variants of uncertain significance it reported, a cohort study of 1.45 million people tested for hereditary cancer found. Most of those tested were women (95.6%). Unique variants first called pathogenic or benign seldom changed clinical category.

Key Findings

Of 26 670 unique variants of uncertain significance, 7.7% (2048) were reclassified. Across all 184 327 reported variants of uncertain significance, 24.9% (46 890) were.
Downgrades to benign or likely benign made up 91.2% (1867 of 2048) of reclassified unique variants. Upgrades to pathogenic or likely pathogenic made up 8.7% (178 of 2048).
The median time to an amended report was 1.17 years for downgraded variants of uncertain significance and 1.86 years for upgraded ones.
Unique variants first called pathogenic or likely pathogenic changed clinical category in 0.7% (61 of 9112). Benign or likely benign variants did so in 0.2% (15 of 8995).
Overall, 6.4% of 44 777 unique variants were reclassified. The laboratory issued 1.67 million initial test reports and 59 955 amended reports due to variant reclassification.

Interpretation

The study is a descriptive cohort built from one commercial laboratory's records. The findings come from a single laboratory, and the authors call for further research on whether they generalize to other laboratories. Clinicians ordered the tests for suspected hereditary cancer, so the group is not a sample of the general population. The authors say the apparent decrease in time to amended reports in later years reflects less time available for review. Clinical follow-up exists only for the 8427 patients at one academic center.

RRM Context

Women made up 95.6% of this laboratory's tested cohort, so the findings bear on women's health care. A variant of uncertain significance is an unresolved test result. Restorative reproductive medicine treats an unresolved result as a reason to keep looking for the cause. The laboratory changed its classifications as new evidence arrived.

Our editorial summary of this paper, not the article's abstract.

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.

Jacqueline Mersch, Nichole Brown, Sara Pirzadeh-Miller, Erin Mundt, Hannah C Cox, Krystal Brown, Melissa Aston, Lisa Esterling, Susan Manley, Theodora Ross

J Mersch, N Brown, S Pirzadeh-Miller, E Mundt, H Cox, K Brown, M Aston, L Esterling, Sue Manley, S Manley, T Ross

PMID 30264118 30264118 DOI 10.1001/jama.2018.13152 10.1001/jama.2018.13152 Mersch et al. 2018, Mersch 2018

Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing

One lab reclassified 24.9% of uncertain hereditary cancer variants

Key Findings

Interpretation

RRM Context

Abstract

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