ClinVar

Description

Variant summary: FANCA c.3430C>T (p.Arg1144Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 1,607,004 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database (v4 dataset), including 2 homozygotes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in FANCA causing Fanconi Anemia (0.0022), however, the presence of the variant in homozygotes, suggests that it might be benign when found in homozygous state. On the other hand, the variant c.3430C>T, has been reported in the literature in a compound heterozygous individual affected with Fanconi Anemia (Gille_2012), who carried a likely pathogenic FANCA variant, although the phase of these variants was not provided. In addition, the variant has been reported in heterozygous state in patients affected with breast cancer and other tumor phenotypes (e.g Penkert_2018, de Angelis de Carvalho_2020). These reports 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: 22778927, 30086788, 32659967). ClinVar contains an entry for this variant (Variation ID: 408171). Based on the evidence outlined above, the variant was classified as uncertain significance.