ClinVar

Description

Variant summary: FANCF c.860A>G (p.Tyr287Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251472 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCF causing Fanconi Anemia (6.4e-05 vs 0.0004), allowing no conclusion about variant significance. c.860A>G has been reported in the literature in individuals affected with head and neck squamous cell carcinoma or Cowden-like syndrome, without evidence for causality (e.g. Chandrasekharappa_2017, Henn_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28678401, 30680046). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.