The Importance of Bioinformatic re-evaluation of variants Detected in 290 Panels/ Exomes at Genetics -Shamir Medical Center

Aim: To specify the reasons for variant re-classifications performed at Shamir MD CTR.

Methods: 290 variants derived from 74 exomes and 88 panels were bioinformatically re-evaluated and re-classified . Period- from May 2018-October 2020, corresponding to 159 index patients (158 families).

Results. Overall, 61/290 (21%) were re-classified.after re-evaluation

Re-classification resulted in increased severity from VUS (Variant of Unknown Significance) to LP (Likely Pathogenic) 13/61 (21.3%), VUS to P (Pathogenic) 4/61 (6.6%). LB (Likely Benign) to VUS in 1/61 (1.6%). Downgrading in re-classification from P/LP to VUS 1 and 2/61(1.6% and 3.3% accordingly): VUS to LB was modified in 14/61 (23%). Modification from LP to P or vice versa appeared in 6 and 3/61 (9.8% and 4.9% respectively).

The decision of re-classification was based on: (1) Bioinformatic data related in 60/61 cases. :. (2) Clinical re-evaluation in 1 index patient out of 61 cases.

Conclusions: Re-classification of 21% of retrieved variants is in line with previous medical literature range (4.7-71.8%). The fact that analyses modified mostly V>LP and V>LB (21.3% and 23% accordingly) highlights the importance of periodic re-assessment on a routine basis as these changes expected to affect clinical genetic counseling. Presented data is relevant to the pediatric physician community as currently exomes and panels are included in health basket for an increasing number of indications, and awareness to possible bioinformatics re-evaluation may uncover new diagnoses that may result in treatments and facilitate family planning.