ClinVar

Description

Variant summary: FANCA c.2602-9_2602-8delCT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, the variant has been shown to cause aberrant splicing in a patient derived cell line carrying the variant (Kimble_2018). The variant allele was found at a frequency of 0.00071 in 251154 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FANCA causing Fanconi Anemia (0.00071 vs 0.0022), allowing no conclusion about variant significance. c.2602-9_2602-8delCT has been reported in the literature in individuals affected with Fanconi Anemia (Kimble_2018) and also in breast cancer patients (Bonache_2018, DelValle_2020, Schubert_2019). These data indicate that the variant may be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely pathogenic (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.