Submissions for variant NM_000110.4(DPYD):c.2303C>A (p.Thr768Lys)

gnomAD frequency: 0.00011  dbSNP: rs56005131

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001788190	SCV002031285	drug response	fluorouracil response - Other	2021-05-25	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Eurofins Ntd Llc (ga)	RCV000281091	SCV000341264	uncertain significance	not provided	2016-04-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000671369	SCV000796338	likely benign	Dihydropyrimidine dehydrogenase deficiency	2017-12-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000671369	SCV001253063	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	RCV000281091	SCV001778862	uncertain significance	not provided	2020-09-02	criteria provided, single submitter	clinical testing	Identified with a second missense variant, phase unknown, in a female Japanese individual with very low dihydropyrimidine dehydrogenase (DPD) activity and protein expression levels (Ogura et al., 2005); Functional studies are discordant in their conclusions regarding enzyme activity (Offer et al., 2014; Ogura et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in the heterozygous state in 3-6% of Japanese individuals (Maekawa et al., 2007; Okamoto et al., 2007); This variant is associated with the following publications: (PMID: 29769267, 20920994, 17876700, 19287123, 17828463, 24163242, 21498394, 16033824, 24648345, 32619063, 32707991)
Ambry Genetics	RCV002518984	SCV003684850	uncertain significance	Inborn genetic diseases	2021-03-02	criteria provided, single submitter	clinical testing	The c.2303C>A (p.T768K) alteration is located in exon 19 (coding exon 19) of the DPYD gene. This alteration results from a C to A substitution at nucleotide position 2303, causing the threonine (T) at amino acid position 768 to be replaced by a lysine (K). The in silico prediction for the p.T768K alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003920127	SCV004731310	likely benign	DPYD-related disorder	2020-04-13	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GenomeConnect, ClinGen	RCV000671369	SCV000840326	not provided	Dihydropyrimidine dehydrogenase deficiency		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.