TY - JOUR
T1 - An Educational Assessment of Evidence Used for Variant Classification
T2 - A Report of the Association for Molecular Pathology
AU - Lyon, Elaine
AU - Temple-Smolkin, Robyn L.
AU - Hegde, Madhuri
AU - Gastier-Foster, Julie M.
AU - Palomaki, Glenn E.
AU - Richards, C. Sue
N1 - Publisher Copyright:
© 2022 Association for Molecular Pathology and American Society for Investigative Pathology
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85131903343&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131903343&partnerID=8YFLogxK
U2 - 10.1016/j.jmoldx.2021.12.014
DO - 10.1016/j.jmoldx.2021.12.014
M3 - Review article
C2 - 35429647
AN - SCOPUS:85131903343
SN - 1525-1578
VL - 24
SP - 555
EP - 565
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
IS - 6
ER -