ClinVar

Description

Variant summary: DPYD c.775A>G (p.Lys259Glu) results in a conservative amino acid change located in the FAD/NAD(P)-binding domain of 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 0.0061 in 251782 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency phenotype (0.0025), strongly suggesting that the variant is benign. c.775A>G has been reported in the literature in individuals affected with 5-FU-related toxicity (example Gross_2003, Schwab_2008, Harismendy_2013, Garcia-Gonzalez_2020). One of these studies described that DPYD enzyme activity measured in the cytosolic fraction of PBMCs from a heterozygous patient was in the normal range (Gross_2003). These reports do not provide unequivocal conclusions about association of the variant with Dihydropyrimidine Dehydrogenase Deficiency. At least one publication reports evaluating the impact of the variant on protein function in an in vitro expression system and found no damaging effect on enzymatic activity (Offer_2014). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three laboratories classified the variant as benign, one as likely benign, and one as VUS. Based on the evidence outlined above, the variant was classified as benign.