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Thesis - Campus Access Only


In 2015, ACMG published guidelines for variant interpretation with the intent of creating a common standard that could be utilized by all genetic testing laboratories. However, many studies have shown that the ACMG guidelines do not offer clear or objective grounds for practice, leading to frequent discordance between laboratories in how a given variant is called. To address the limitations of ACMG’s guidelines, the genetic testing laboratory Invitae developed a variant interpretation semi- quantitative framework called Sherloc. Sherloc’s algorithm includes two categories of phenotypic evidence that can be utilized toward establishing pathogenicity for variants found in a patient: case reports and pathognomonics. Applicable case report evidence includes case reports where phenotypic symptoms are present and indicate that an individual would be expected to receive a molecular diagnosis from genetic testing 25% to 75% of the time, for the set of genes that the patient was tested. Pathognomonic evidence can be applied if the presence of the symptom or feature defined as pathognomonic has been proven to result in a molecular diagnostic yield of >75% using the relevant gene or panel test. In this study, concordance and discordance were assessed between classifications made using three systems: the ACMG guidelines, Sherloc with case report criteria only (Case Only), and Sherloc with case report and pathognomonic criteria (Computed). When these three systems were compared, Case Only and Computed criteria lowered the percentage of variants classified as a VUS (from 54% to 20%) or likely pathogenic (from 20% to 13%) while increasing the percentage of pathogenic classifications (from 26% to 67%) when compared to classifications by the ACMG guidelines alone. Moreover, 34% of the unique variants in 2 genes where pathognomonic criteria had been established had a clinically significant upgrade with the potential to impact patient care. Overall, efforts should be made to expand the number of genes across specialties that incorporate pathognomonic criteria to assist the variant interpretation process.