The DPYD NM_000110.4:c.1905+1G>A (NP_000101.2:p.?) splicing variant has previously been reported in somatic cancers (COSMIC; COSV106516976, n = 6 times). This variant is predicted to disrupt normal RNA processing, resulting in either an aberrant protein product or nonsense-mediated RNA decay. Experimental evidence: Direct RNA analysis showed exon-14 skipping with a 165-bp deletion, and enzyme testing found reduced DPD activity in variant carriers. Based on available guidelines, this variant is considered to be Pathogenic. This variant is considered to be drug response by the VCEP (ClinPGx; ClinVar ID 432).
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.DPYD encodes dihydropyrimidine dehydrogenase, an enzyme that initiates and controls the breakdown of the pyrimidines uracil and thymidine. Reduced DPYD activity causes dihydropyrimidine dehydrogenase deficiency, which can lead to abnormal uracil and thymine metabolism and a higher risk of severe toxicity from 5-fluorouracil chemotherapy. DPYD is infrequently altered in cancer and is not established as an oncogene or tumor suppressor.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, very strong: canonical +1 splice disruption causes complete exon 14 skipping and loss of functional DPD, with DPYD loss of function established as a disease mechanism.
Met, strong: direct RNA analysis showed exon-14 skipping with a 165-bp deletion, and enzyme testing found reduced DPD activity in variant carriers.
Met: 12/227 cases versus 2/192 controls gives OR 5.30 (95% CI 1.17–23.99), exceeding the >5.0 threshold with a confidence interval excluding 1.
Met: affected DPYD patients included compound heterozygous ΔEX14/C29R and multiple homozygous ΔEX14/ΔEX14 genotypes.
Met at moderate strength: SpliceAI max delta 0.993 meets the >=0.5 generic PP3 threshold for an intronic splice-site variant.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PVS1 very strong plus PS3 and PS4 strong satisfy the generic ACMG/AMP Pathogenic rule, with additional PM3 and PP3 moderate evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 8,167 / 1,613,786 alleles. Recorded AF 0.00506077. Recorded homozygote count 41.
This variant is present in gnomAD v2.1 (AF= 0.00568881; MAF= 0.56888%, 1608/282660 alleles, homozygotes = 9) and has highest observed frequency in the European (Finnish) population (AF= 0.0238455; MAF= 2.38455%, 599/25120 alleles, homozygotes = 6); grpmax FAF= 0.00599085.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0035834509718753395, 66/18418 alleles, homozygotes = 0).
Recorded SpliceAI maximum delta score: 0.993. Refer to the recorded PP3/BP4 rationale for interpretation.
22 Pathogenic · 1 Benign. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV106516976, n = 6 times).
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 6 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
None of PS2, PM6, PP1, or BS4 is assigned because the reviewed evidence does not document the required de novo, affected-relative segregation, or affected-relative non-segregation observations.
The available family evidence concerns an autosomal-recessive DPYD disorder with one reported homozygous affected index patient and carrier relatives, not an informative dominant segregation analysis.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
PS4 is supported by a direct case-control comparison for the exact variant; PP4 and BP5 remain unassessed because the individual case phenotype and alternate molecular diagnosis are not supplied; PP5 and BP6 are not met because the exact-variant ClinVar expert-panel classification is drug response rather than the required pathogenic or benign classification.
No criteria match.
PVS1 is met at full strength. NM_000110.4:c.1905+1G>A is a canonical splice-donor +1 variant in DPYD, and DPYD loss of function is supported as a germline disease mechanism. The variant is relevant to the principal DPYD transcript (NM_000110.4) and affects exon 14 of 23, not the first, last, or penultimate exon. Direct transcript studies show complete skipping of exon 14, removing 165 bp encoding amino acids 581–635; the deletion is in-frame rather than an NMD-generating frameshift, but the reported consequence is loss of functional DPD expression/complete loss of DPD activity. Exon 14 is internal and the evidence supports a null functional outcome, with no evidence that this is a non-critical distal exon or a repeat-region artifact. No named downgrade rule supplied for PVS1 applies.
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
PS3 is met at strong strength. The exact variant, reported historically as IVS14+1G>A, was evaluated in direct functional studies. RT-PCR/mRNA analysis demonstrated skipping of DPYD exon 14 with loss of a 165-bp transcript segment encoding amino acids 581–635 (PMID:10071185). In a cohort of 60 patients with severe grade 3–4 fluorouracil toxicity, DPD activity was measured by radiochemical assay; the variant was enriched among patients with reduced activity (15/36 heterozygotes and 1/36 homozygote among those below 70% of control activity versus 1/24 heterozygotes among those with normal activity), and the study reports exon-14 skipping as the molecular consequence (PMID:12360106). These results directly show abnormal splicing and reduced biologically relevant DPYD enzyme function, satisfying the definition of well-established functional evidence supportive of a damaging effect. The evidence is convergent across RNA and enzyme-activity endpoints, although no single study establishes validation in a clinical diagnostic laboratory setting.
PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PS4 is met at strong strength. PMID:23603345 directly reports the exact variant as IVS14+1G>A in 12/227 patients with grade 3/4 fluoropyrimidine toxicity and 2/192 untreated Caucasian controls. Treating these as a 2x2 case-control table gives OR=(12x190)/(215x2)=5.3023, with a Wald 95% CI of 1.1718-23.9936; the CI excludes 1. The governing ACMG/AMP threshold is >5.0 with a confidence interval that does not include 1. I also checked the other literature_pass PS4 lead, PMID:10071185: it reports 23/44 mutant alleles in 22 affected patients but has no unaffected or population control comparison, so it was not used as the case-control estimate.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM3 is met for this autosomal-recessive DPYD deficiency variant. Van Kuilenburg et al. reviewed 17 families with 22 patients with complete DPD deficiency and reported the target allele, IVS14+1G>A (equivalent to NM_000110.4:c.1905+1G>A), in homozygous patients and in compound-heterozygous genotypes, including patient 14.1 with C29R/ΔEX14. The paper reports that C29R, like the target splice-site allele, is an identified mutant allele associated with complete DPD deficiency and that family-member analysis showed recessive segregation. The compound-heterozygous genotype places the target allele in trans with the other disease-associated allele, satisfying PM3; the homozygous affected observations provide additional recessive allelic evidence.
PM3: For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase.
The variant is NM_000110.4:c.1905+1G>A, a canonical splice-donor/intronic variant, so the applicable generic PP3/BP4 path is SpliceAI only; REVEL is not applicable and BayesDel is not available for generic ACMG strength calibration. SpliceAI max delta is 0.993, which meets the generic PP3 moderate threshold of >=0.5 from the supplied ClinGen SVI calibration, so PP3 is met at moderate strength. The same SpliceAI prediction is not double-counted for BP4.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
PM2 is not met. The generic supporting threshold supplied for this case is <=0.0001, but the variant is present at AF=0.00568881 in gnomAD v2.1 and AF=0.00506077 in gnomAD v4.1, so the result is not an absence or extremely low frequency in controls.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PP5 is not met under the supplied generic rule. ClinVar identifies the exact variant as reviewed by an expert panel for drug response, not as Pathogenic or Likely pathogenic. A single-laboratory Pathogenic submission and published pathogenic descriptions do not satisfy the required exact-variant ClinVar expert-panel classification condition.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.
BA1 is not met. Under the generic ACMG/AMP stand-alone threshold of >=0.05, the highest observed all-comers allele frequency is 0.02384554 in the gnomAD v2.1 Finnish subgroup and 0.02333281 in gnomAD v4.1; the overall frequencies are 0.00568881 and 0.00506077, respectively. No governing VCEP specifies a different population source, and none of these frequencies reaches 5%.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS3 is not met. The available variant-specific functional evidence does not show no damaging effect on protein function or splicing; instead, it shows exon-14 skipping and reduced DPD activity. PMID:23335937 explicitly states that no functional test could be performed in its reported family, so that report cannot support BS3. No validated benign functional assay with appropriate controls demonstrating normal DPYD splicing or enzyme function for c.1905+1G>A was identified.
BS3: Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a canonical splice-donor/intronic variant, so the applicable generic BP4 path is SpliceAI only; REVEL is not applicable and BayesDel is not available for generic ACMG strength calibration. SpliceAI max delta is 0.993, which is above the generic BP4 supporting threshold of <=0.1 from the supplied ClinGen SVI calibration, so BP4 is not met. The SpliceAI prediction is used only once and is not double-counted with PP3.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP6 is not met under the supplied generic rule. ClinVar's exact-variant expert-panel record is classified as drug response, not Benign or Likely benign. The one ordinary-laboratory Benign assertion and aggregate conflicting submissions cannot trigger BP6.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6. Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger either criterion.
No qualifying de novo observation is documented. The available family report describes a homozygous affected index patient with both sons heterozygous for the variant, but does not establish maternity and paternity confirmation for a de novo event in an affected patient.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No assumed de novo occurrence is documented. The available report describes familial transmission in an affected homozygous patient and heterozygous offspring, but does not provide a de novo observation lacking parental confirmation.
Assumed de novo, but without confirmation of paternity and maternity.
The available literature describes affected patients across families and a family with one homozygous affected index patient and heterozygous relatives, but it does not provide multiple affected family members with variant-positive cosegregation suitable for PP1. The reported DPYD disorder is recessive, so carrier status in unaffected relatives is not qualifying affected-member segregation.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The available literature describes DPD deficiency and fluoropyrimidine toxicity associated with this variant, but the case materials do not provide a sufficiently specific phenotype or family history for the individual being interpreted. Therefore, the highly specific phenotype requirement cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS1 cannot be adjudicated from the default 1% threshold alone. The overall allele frequency is 0.00568881 in gnomAD v2.1 and 0.00506077 in gnomAD v4.1, while the Finnish subgroup is approximately 2.4%. This ancestry-enriched frequency could be compatible with a reduced-penetrance, exposure-dependent DPYD pharmacogenetic phenotype, but the case does not provide the disease prevalence, penetrance, allelic heterogeneity, or other inputs needed for a maximum credible allele-frequency calculation under Whiffin et al. 2017. Therefore BS1 is not assessed rather than applied from the 1% default alone.
Allele frequency is greater than expected for the disorder.
No informative affected relatives who lack the variant are documented. The reported wild-type sister is not established to be affected, and the heterozygous sons are not documented as affected relatives; therefore the evidence does not demonstrate lack of segregation in affected family members.
Lack of segregation in affected members of a family.
BP2 cannot be assessed from the available evidence. The reviewed reports document homozygous and compound-heterozygous disease-associated DPYD genotypes, including the target allele in trans in a recessive context, but do not report the target allele in cis with a pathogenic variant. The case does not establish a fully penetrant dominant DPYD disorder or provide a qualifying cis observation.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
No case-specific evidence was found showing that this variant occurred in a patient whose disease had an alternate molecular basis. Published toxicity and DPD-deficiency observations do not establish an alternate molecular cause for the interpreted case.
Variant found in a case with an alternate molecular basis for disease.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PS1 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM1 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM5 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PP2 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BS2 is not applicable under the supplied generic definition because it requires observation in a healthy adult for a disorder with full penetrance expected at an early age. DPYD-related fluoropyrimidine toxicity is exposure-dependent and the case does not establish full early-age penetrance; gnomAD homozygotes therefore do not satisfy the stated BS2 applicability condition.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP1 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in DPYD, mapped onto the exon structure of NM_000110.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (Finnish)1494 / 64,030 | 0.02318 hom |
| Ashkenazi Jewish165 / 29,590 | 0.0056 |
| Remaining individuals313 / 62,484 | 0.005 |
| European (non-Finnish)5701 / 1,179,786 | 0.004816 hom |
| South Asian364 / 91,080 | 0.0047 hom |
| Middle Eastern17 / 6,058 | 0.0028 |
| Admixed American77 / 59,964 | 0.0013 |
| African/African American36 / 75,016 | 0.00048 |
| European (Finnish)599 / 25,120 | 0.0246 hom |
| European (non-Finnish)731 / 129,050 | 0.00571 hom |
| Remaining individuals39 / 7,214 | 0.0054 |
| Ashkenazi Jewish53 / 10,366 | 0.0051 |
| South Asian132 / 30,612 | 0.00432 hom |
| Admixed American40 / 35,378 | 0.0011 |
| African/African American14 / 24,970 | 0.00056 |
This variant is present in gnomAD v4.1 (AF= 0.00506077; MAF= 0.50608%, 8167/1613786 alleles, homozygotes = 41) and has highest observed frequency in the European (Finnish) population (AF= 0.0233328; MAF= 2.33328%, 1494/64030 alleles, homozygotes = 18); grpmax FAF= 0.00472664.
This variant is present in gnomAD v2.1 (AF= 0.00568881; MAF= 0.56888%, 1608/282660 alleles, homozygotes = 9) and has highest observed frequency in the European (Finnish) population (AF= 0.0238455; MAF= 2.38455%, 599/25120 alleles, homozygotes = 6); grpmax FAF= 0.00599085.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0035834509718753395, 66/18418 alleles, homozygotes = 0).
The variant is NM_000110.4:c.1905+1G>A, a canonical splice-donor/intronic variant, so the applicable generic PP3/BP4 path is SpliceAI only; REVEL is not applicable and BayesDel is not available for generic ACMG strength calibration. SpliceAI max delta is 0.993, which meets the generic PP3 moderate threshold of >=0.5 from the supplied ClinGen SVI calibration, so PP3 is met at moderate strength. The same SpliceAI prediction is not double-counted for BP4.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a canonical splice-donor/intronic variant, so the applicable generic BP4 path is SpliceAI only; REVEL is not applicable and BayesDel is not available for generic ACMG strength calibration. SpliceAI max delta is 0.993, which is above the generic BP4 supporting threshold of <=0.1 from the supplied ClinGen SVI calibration, so BP4 is not met. The SpliceAI prediction is used only once and is not double-counted with PP3.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000110.4:c.1905+1G>A in DPYD is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000101.2:p.?. As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for DPYD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.66.
12 paper records listed. 4 cited in the classification.
The G→A point mutation changes an invariant GT splice donor site to AT; this leads to the skipping of exon 14 immediately upstream of the mutated splice donor site, during the splicing of DPD pre-mRNA. As a consequence, a 165-bp fragment encoding amino acid residues 581–635 of the primary sequence of the DPD protein is lacking in the mature DPD mRNA.
Location DPD mutations in patients with DPD deficiency; Table 1; Table 2; Phenotype-genotype relationship
Context Review of 17 families comprising 22 patients with complete DPD deficiency; mutation identification, segregation analysis, and assessment of the splice and protein consequences.
This mutation leads to skipping of exon 14 immediately upstream of the mutated splice donor site in the process of DPD pre-mRNA splicing.
Location Discussion, paragraph describing the molecular consequence of IVS14 + 1G>A; Results/Table 1 for genotype frequencies and DPD activity groups
Context Cohort of 60 cancer patients with severe grade 3–4 5-fluorouracil-associated toxicity; DPD activity was measured in peripheral blood mononuclear cells and the variant was detected by restriction fragment length polymorphism analysis.
Direct sequencing of the 239-bp amplicon containing the DPYD exon 14 coding and flanking intron region revealed that the index patient was homozygous for the c.1905+1G>A mutation (II.2 in Figures 1, 2). Although no functional test could be performed due to unavailability of fresh blood samples, DPD activity was assumed to be completely absent according to a prior study describing the fatal outcome of a c.1905+1G>A homozygous patient with no significant residual activity of DPD in peripheral blood mononuclear cells and fibroblasts.
Location Introduction, paragraphs 3–5 and 8; Results, Clinical evaluation and Sequence analysis of the DPYD gene; Figures 1–3
Context PCR amplification and direct sequencing of a DPYD exon 14 amplicon, family segregation analysis, and high-resolution melting assay; the report describes a severe 5-fluorouracil toxicity case.
Among 227 patients from the toxicity group, 27 (12%) had deleterious mutations in DPYD: twelve (5%) had IVS14 +1 G>A, eleven (5%) had D949V and four (2%) had other mutations. Only 7/192 (4%) patients from the control group had DPYD genotype abnormalities: two (1%) had IVS14 +1 G>A, four (2%) had D949V and one (1%) had other mutation.
Location Abstract
Context Full DPYD sequencing in untreated Caucasian controls and Caucasian patients with grade 3/4 fluoropyrimidine toxicity.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00506077; MAF= 0.50608%, 8167/1613786 alleles, homozygotes = 41) and has highest observed frequency in the European (Finnish) population (AF= 0.0233328; MAF= 2.33328%, 1494/64030 alleles, homozygotes = 18); grpmax FAF= 0.00472664.
This variant is present in gnomAD v2.1 (AF= 0.00568881; MAF= 0.56888%, 1608/282660 alleles, homozygotes = 9) and has highest observed frequency in the European (Finnish) population (AF= 0.0238455; MAF= 2.38455%, 599/25120 alleles, homozygotes = 6); grpmax FAF= 0.00599085.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0035834509718753395, 66/18418 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Pathogenic (22 clinical laboratories) and as Benign (1 clinical laboratory) and as drug response by ClinPGx (expert panel). (ClinVarID = 432)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.66.
This variant has previously been reported in somatic cancers (COSMIC; COSV106516976, n = 6 times).