chr1-97515787-A-C

Variant names:

• chr1-97515787-A-C
• rs55886062
• NM_000110.4:c.1679T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3 PP5_Strong

The NM_000110.4(DPYD):​c.1679T>G​(p.Ile560Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000655 in 1,612,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: DPYD NM_000110.4 missense
• Clinical Significance: drug response reviewed by expert panel P:11 O:5
• Conservation: PhyloP100: 8.76

Genes affected

DPYD (HGNC:3012): (dihydropyrimidine dehydrogenase) The protein encoded by this gene is a pyrimidine catabolic enzyme and the initial and rate-limiting factor in the pathway of uracil and thymidine catabolism. Mutations in this gene result in dihydropyrimidine dehydrogenase deficiency, an error in pyrimidine metabolism associated with thymine-uraciluria and an increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant 1-97515787-A-C is Pathogenic according to our data. Variant chr1-97515787-A-C is described in ClinVar as [drug_response]. Clinvar id is 88975.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, drug_response=4, Pathogenic=5, not_provided=1}. Variant chr1-97515787-A-C is described in Lovd as [Pathogenic]. Variant chr1-97515787-A-C is described in Lovd as [Benign]. Variant chr1-97515787-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYD	NM_000110.4	c.1679T>G	p.Ile560Ser	missense_variant	Exon 13 of 23	ENST00000370192.8	NP_000101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYD	ENST00000370192.8	c.1679T>G	p.Ile560Ser	missense_variant	Exon 13 of 23	1	NM_000110.4	ENSP00000359211.3

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000319 AC: 80 AN: 250646 Hom.: 0 AF XY: 0.000310 AC XY: 42 AN XY: 135408

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000654

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000682 AC: 997 AN: 1460868 Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 459 AN XY: 726764

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000853

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74380

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000632 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000655

EpiControl AF: 0.000830

ClinVar

Significance: drug response

Submissions summary: Pathogenic:11 Other:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5 Other:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DPYD: PS3:Very Strong, PM2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diasio Lab, Mayo Clinic

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the heterozygous state in patients with partial DPD deficiency, including patients who experienced 5-FU toxicity during cancer treatment (PMID: 10803677, 26265035); Published functional studies demonstrate that this variant reduces DPD enzyme activity (PMID: 23328581); 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: 25381393, 11895907, 19795123, 26603945, 37101114, 26265035, 32595208, 10803677, 23328581) -

Dihydropyrimidine dehydrogenase deficiency Pathogenic:5

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity (MIM#274270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 11783493). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 88 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated dihydroorotate dehydrogenase domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals and it is also a known risk for 5-fluorouracil toxicity (ClinVar, LOVD, PMIDs: 11895907, 11783493, 26603945). As DPYD variants that result in reduced enzyme function place individuals at risk of fluoropyrimidine toxicity, formal pharmocogenomic studies are recommended prior to treatment with fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies show up to a 75% reduction in activity relative to wild-type (PMID: 23328581, 29152729). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 27, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DPYD c.1679T>G (p.Ile560Ser) results in a non-conservative amino acid change located in the dihydroorotate dehydrogenase domain (IPR005720) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 250646 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in DPYD causing Dihydropyrimidine Dehydrogenase Deficiency (0.00032 vs 0.0025), allowing no conclusion about variant significance. The variant, c.1679T>G (also described as DPYD*13), has been reported in the literature in a compound heterozygous individual affected with childhood onset Dihydropyrimidine Dehydrogenase Deficiency (van Kuilenburg 2002), and in other compound heterozygous individuals who had severe 5-fluorouracil toxicity following chemotherapy, but not other clinical symptoms or abnormalities were noted (Johnson_2002, Thomas_2015). In addition, the variant was also reported in several heterozygous individuals affected with 5-fluorouracil toxicity following chemotherapy (see e.g. Thomas_2015), and a meta-analysis found that the variant in heterozygosity was significantly associated with fluoropyrimidine-associated toxicity (adjusted relative risk (RR): 4.40, 95% CI: 2.08-9.30, p<0.0001), though the presence of this variant does not always resulted in toxicity (Meulendijks_2015). Experimental evidence evaluating an impact on protein function demonstrated that the variant resulted in a decreased enzyme activity, corresponding to about 75% reduction relative to the WT (Offer_2014), in addition, enzyme activity measured from patient derived peripheral blood mononuclear cells (PBMs) in a compound heterozygous patient was found almost undetectably low (van Kuilenburg 2002). Several Pharmacogenetics groups, including the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Dutch Pharmacogenetics Working Group (DPWG), and the Swiss Group of Pharmacogenomics and Personalised Therapy (SPT), released recent guidelines, considering this variant to be a 'non-functional' allele (with an activity score of 0), and strongly recommending DPYD genotyping for this and a few other variants, prior to the start of therapy with fluoropyrimidines, and a reduction of the initial dose in genotyped-positive patients in order to decrease the risk of fluoropyrimidine-induced toxicity (Caudle_2013, Amstutz_2018, Lunenburg_2020, Hamzic_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=1) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Apr 05, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1679T>G (p.I560S) alteration is located in exon 13 (coding exon 13) of the DPYD gene. This alteration results from a T to G substitution at nucleotide position 1679, causing the isoleucine (I) at amino acid position 560 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.031% (88/282028) total alleles studied. The highest observed frequency was 0.062% (80/128610) of European (non-Finnish) alleles. This alteration was detected in conjunction with another alteration in DPYD in multiple individuals with Dihydropyrimidine dehydrogenase deficiency (van Kuilenburg, 2000; Johnson, 2002; Thomas, 2016). This amino acid position is highly conserved in available vertebrate species. In an assay testing DPYD function, this variant showed a functionally abnormal result (Offer, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

tegafur response - Toxicity Other:1

May 26, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: 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. Drug-variant association: Toxicity

fluorouracil response - Toxicity Other:1

May 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: 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. Drug-variant association: Toxicity

fluorouracil response - Other Other:1

May 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: 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. Drug-variant association: Other

capecitabine response - Toxicity Other:1

May 24, 2021

PharmGKB

Significance: drug response

Review Status: reviewed by expert panel

Collection Method: 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. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.99
MPC		0.39
ClinPred		0.82	D
GERP RS		5.2
Varity_R		0.70
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55886062; hg19: chr1-97981343; COSMIC: COSV104426937;