Submissions for variant NM_000110.4(DPYD):c.775A>G (p.Lys259Glu)

gnomAD frequency: 0.00513  dbSNP: rs45589337

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224513	SCV000281065	likely benign	not provided	2016-04-21	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
PreventionGenetics, part of Exact Sciences	RCV000249889	SCV000302306	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000249889	SCV000700574	benign	not specified	2016-11-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000249889	SCV000917305	benign	not specified	2022-06-21	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000986378	SCV001135368	benign	Dihydropyrimidine dehydrogenase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986378	SCV001259747	uncertain significance	Dihydropyrimidine dehydrogenase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000224513	SCV001893792	benign	not provided	2020-11-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22935545, 14635116, 19473056, 24648345)
Ambry Genetics	RCV002408943	SCV002672183	likely benign	Inborn genetic diseases	2018-03-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000224513	SCV004124099	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	DPYD: BS1, BS2