An Educational Assessment of Evidence Used for Variant Classification: A Report of the Association for Molecular Pathology

Elaine Lyon, Robyn L. Temple-Smolkin, Madhuri Hegde, Julie M. Gastier-Foster, Glenn E. Palomaki, C. Sue Richards

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations


The Association for Molecular Pathology Variant Interpretation Testing Among Laboratories (VITAL) Working Group convened to evaluate the Standards and Guidelines for the Interpretation of Sequence Variants implementation into clinical practice, identify problematic classification rules, and define implementation challenges. Variants and associated clinical information were provided to volunteer respondents. Participant variant classifications were compared with intended consensus-derived classifications of the Working Group. The 24 variant challenges received 1379 responses; 1119 agreed with the intended response (81%; 95% CI, 79% to 83%). Agreement ranged from 44% to 100%, with 16 challenges (67%; 47% to 82%) reaching consensus (≥80% agreement). Participant classifications were also compared to a calculated interpretation of the ACMG Guidelines using the participant-reported criteria as input. The 24 variant challenges had 1368 responses with specific evidence provided and 1121 (82%; 80% to 84%) agreed with the calculated interpretation. Agreement for challenges ranged from 63% to 98%; 15 (63%; 43% to 79%) reaching consensus. Among 81 individual participants, 32 (40%; 30% to 50%) reached agreement with at least 80% of the intended classifications and 42 (52%; 41% to 62%) with the calculated classifications. This study demonstrated that although variant classification remains challenging, published guidelines are being utilized and adapted to improve variant calling consensus. This study identified situations where clarifications are warranted and provides a model for competency assessment.

Original languageEnglish (US)
Pages (from-to)555-565
Number of pages11
JournalJournal of Molecular Diagnostics
Issue number6
StatePublished - Jun 2022

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Medicine


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