Observed frequency and challenges of variant reclassification in a hereditary cancer clinic

Abstract

PurposeEfforts have been made by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology to make variant classification more uniform, but many limitations remain. Reclassification of a variant of uncertain significance (VUS) is expected, but other more certain calls, like pathogenic or benign, can also be reclassified once additional information is gathered. Variant reclassification can create difficult circumstances for both patients and clinicians.MethodsRetrospective review of all variant reclassifications in genes associated with hereditary cancer syndromes at one clinic between September 2013 and February 2017 was completed. All variant reclassifications were completed and reported by the original testing laboratory.ResultsA total of 1,103 hereditary cancer tests were ordered. Fewer than 5% (40/1,103) of the initial reports were updated during that time period. Most reclassifications (29/40) were downgrades of VUS to likely benign. Only three reclassifications could potentially alter medical management.ConclusionThe majority of variant reclassifications do not impact medical management. Upgrading a variant call to pathogenic could be important for a patient's care and shows the importance of open communication between laboratories and clinicians. A variant downgrade from pathogenic can be a significant reclassification as well, especially if prophylactic surgery has been completed.

Biochemical and structural characterization of two variants of uncertain significance in the PMS2 gene

“…The VUS category is a necessary tier within the genetic variant classification system when there is a lack of supporting data to classify a variant as benign or pathogenic (Morris, Hughes, Rosenthal, Gutin, & Bowles, ). The accurate, evidence‐based characterization of VUSs as either pathogenic or benign is clinically necessary to help with the medical management of patients and families (Macklin et al., ). Misclassification of a benign variant as pathogenic could lead to costly and unnecessary screening, chemoprevention, and prophylactic surgeries.…”

“…This tier must be utilized when there is a lack of information that would otherwise classify the variant as either pathogenic (i.e., disease causing) or benign (i.e., does not result in disease). A VUS result can often hinder appropriate medical management of patients undergoing genetic testing for hereditary cancer syndromes (Hoffman-Andrews, 2017;Macklin, Durand, Atwal, & Hines, 2018). Lynch syndrome (LS) is an autosomal dominant cancer syndrome that predisposes individuals to a higher lifetime risk for developing colorectal (CRC), endometrial, gastric, biliary tract, and other cancers (Lynch, Snyder, Shaw, Heinen, & Hitchins, 2015;Sehgal et al, 2014).…”

Family communication and patient distress after germline genetic testing in individuals with pancreatic ductal adenocarcinoma

“…A negative result can provide reassurance to other family members regarding a lower likelihood of a hereditary cancer predisposition, suggesting that testing family members is not necessary. Although the majority of reclassified VUS results are downgraded to benign polymorphisms, some will be reclassified to likely pathogenic and become relevant for family members . The reclassification process can take years, at which point the patient may have died.…”

“…Although the majority of reclassified VUS results are downgraded to benign polymorphisms, some will be reclassified to likely pathogenic and become relevant for family members. 35 The reclassification process can take years, at which point the patient may have died. Lower disclosure rates among the patients with negative and VUS genetic testing results suggest that providers need to express the importance of disclosing not only a positive result but also negative and uncertain results to family members.…”

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

“…Third, the chances of finding variants of uncertain significance (VUS), whose biological and clinical value is unknown, are much higher as the number of genes being tested increases . This adds a piece of complexity to genetic counseling and makes interpretation of results more difficult and time‐consuming for laboratories . All the above factors may increase uncertainty and distress in patients who undergo panel testing …”