ClinVar

Description

The FANCC p.Lys545Arg variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs571668582) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 12 of 246178 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 11 of 30776 chromosomes (freq: 0.0004), European in 1 of 111666 chromosomes (freq: 0.000009), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Latino, and Other populations. The p.Lys545 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.