Supplementary Table. Common Names and Corresponding HGVS Nomenclature of Major
Variant CYP2D6 Alleles
Major Nucleotide Variation
Common Name
Effect on Protein
Variant
(GenBank
dbSNP
HGVS
(NCBI RefSeq
Allelea Accession Number
Numberb
(NCBI RefSeq NM_000106.4)
NP_000097.2)
M33388)
rs16947;
p.Arg296Cys;
2850C>T; 4180G>C
c.886C>T; c.1457G>C
*2c
rs1135840
p.Ser486Thr
2549delA
rs35742686
c.775delA
p.Arg259Glyfs
*3
1846G>A
rs3892097
c.506-1G>A
Splicing defect
*4
full gene deletion
*5
1707delT
rs5030655
c.454delT
p.Trp152Glyfs
*6
2935A>C
rs5030867
c.971A>C
p.His324Pro
*7
1758G>T
c.505G>T
p.Gly169X
*8
2615_2617delAAG rs5030656
c.841_843delAAG
p.Lys281delLys
*9
100C>T
rs1065852
c.100C>T
p.Pro34Ser
*10
883G>C
rs5030863
c.181-1G>C
Splicing defect
*11
124G>A
rs5030862
c.124G>A
p.Gly42Arg
*12
1758G>A
rs5030865
c.505G>A
p.Gly169Arg
*14
137_138insT
rs72549357
c.137delTinsTT
p.Leu46Argfs
*15
1023C>T
rs28371706
c.320C>T
p.Thr107Ile
*17
2539_2542delAACT rs72549353
c.765_768delAACT
p.Leu255_Thr256?fs
*19
1973_1974insG
rs72549354
c.632_633insG
p.Glu211?fs
*20
3183G>A
rs59421388
c.1012G>A
p.Val338Met
*29
31G>A
rs769258
c.31G>A
p.Val11Met
*35
100C>T; exon 9
gene conversion to
rs1065852
c.100C>T
p.Pro34Ser
*36
CYP2D7
1863_1864ins(TTT
rs72549356 c.522_523insTTTCGCCCCTTTCGCCCC p.Pro174_Asn175?
*40
CGC CCC)2
2988G>A
rs28371725
c.985+39G>A
Splicing defect
*41
HGVS: Human Genome Variation Society
a
Only the major SNP of the haplotype is given in this table. See the Cytochrome P450
Nomenclature Database website for complete haplotype definitions
(http://www.cypalleles.ki.se/cyp2d6.htm)
b
RefSNP accession ID number (http://www.ncbi.nlm.nih.gov/snp)
c
The CYP2D6*2 nucleotide variants (rs16947; rs1135840) also occur on several other CYP2D6
alleles.
1
Appendix A.
The Laboratory
1111 Laboratory Avenue
Nowhere, State 00839
(555) 920-3333
www.______.com
Patient Name:
ID number:
DOB:
Gender:
Ordering Physician:
Date of Report:
Jane D.
057398468
04/05/2007
Female
Dr. Good
June 15, 2010
Patient Information
Race/Ethnicity:
Family History:
Personal History:
Concurrent Medications:
Test Performed:
CYP2D6
Indication for testing: Predictive response to tamoxifen
Specimen Type:
Blood
Result:
Interpretation:
No Variants Detected
Consistent with an Extensive (Normal) Metabolizer Phenotype.
No cytochrome P450 2D6 mutations were detected. This result is consistent with two copies of functional alleles
and predicts an extensive (normal) metabolizer phenotype.
Drug metabolism may be affected by genetic and non-genetic factors not detected by this assay. For example, coadministration of drugs that inhibit CYP2D6 activity (e.g. some antidepressants) could impair or prevent metabolism
of drugs metabolized by CYP2D6 (e.g. tamoxifen).
This result does not rule out the presence of other mutations within the cytochrome P450 family or other genetic
changes that can affect drug metabolism. It is possible that the individual has a rare variant in the CYP2D6 gene
that is not examined by this assay.
Reference: Ingelman-Sundberg M, Daly AK, Nebert DW, Eds. 2009. Available in:
http://www.imm.ki.se/CYPalleles.
Guidance:

With an extensive metabolizer phenotype, Tamoxifen treatment can follow standard dosing
procedures.

Patient may need to avoid CYP2D6 inhibitors, such as Fluoxetine, Paroxetine, Quinidine, or
Bupropion. A list of CY2D6 metabolizing drugs is available at http://medicine.iupui.edu/clinpharm/ddis/table.asp.

Additional information regarding this test is available from the laboratory (phone number)
This report was reviewed and approved by:
__________________
John Doe, M.D., Ph.D.
Director, The Laboratory
__________
Date
2
Supplemental Information For Cytochrome P450 2D6 (CYP2D6):
The cytochrome P450 gene products are responsible for metabolizing a large number of widely
prescribed drugs. Tamoxifen is metabolized by CYP2D6 to its active form endoxifen.
Individuals with poor metabolizer phenotype for CYP2D6 will require alternative therapies to
Tamoxifen such as aromatase inhibitors, while those with ultra-extensive metabolizer phenotype
will require a decreased Tamoxifen dosage due to higher than normal rates of drug metabolism*.
Variants Tested: All common and most rare alleles with known clinical significance. Allele
defining variant is in bold.
VARIANTS TESTED:
Functional
Nonfunctional
Decreased
Function
Duplicated
Functional
Cyp2D6*1
Cyp2D6*4ABDJK
Cyp2D6*9
Cyp2D6*1xN
(presumed)
100C>T, 1039C>T,
1661G>C, 1846G>A,
2850C>T, 4180G>C
26132615delAGA
(presumed)
Cyp2D6*5
Cyp2D6*10
100C>T,
1039C>T,
1661G>C,
4180G>C
-1584C>G (*2A
only),
1039C>T,
1661G>C, 2850C>T,
4180G>C
Cyp2D6*17
Cyp2D6*35xN
1023C>T,
1661G>C,
2850C>T,
4180G>C
-1584C,
31G>A, 1661G>C,
2850C>T, 4180G>C
Cyp2D6*2ABD
-1584C>G (*2A only),
1039C>T, 1661G>C,
2850C>T, 4180G>C
(deletion)
Cyp2D6*35
Cyp2D6*6ABC
-1584C, 31G>A,
1661G>C, 2850C>T,
4180G>C
1707delT, 1976G>A,
4180G>C
Cyp2D6*7
2935A>C
Cyp2D6*8
1661G>C, 1758G>T,
2850C>T, 4180G>C
Cyp2D6*20
138insT
1661G>C,
1973insG,
1978C>T,
1979T>C,
2850C>T,
4180G>C
Cyp2D6*19
Cyp2D6*29
1661G>C, 25392542delAACT, 2850C>T,
4180G>C
1659G>A,
1661G>C,
2850C>T,
3183G>A,
4180G>C
Cyp2D6*11
883G>C, 1661G>C,
2850C>T, 4180G>C
Cyp2D6*15
Cyp2D6*20
1661G>C, 1973insG,
1978C>T, 1979T>C,
2850C>T, 4180G>C
Cyp2D6*36
100C>T, 1039C>T,
1661G>C, 4180G>C, (gene
conversion to CYP2D7 in
exon 9)
Cyp2D6*2xN
Duplicated
Decreased/
NonFunctional
Cyp2D6*4xN
100C>T, 1039C>T,
1661G>C, 1846G>A,
2850C>T, 4180G>C
Cyp2D6*10xN
100C>T, 1039C>T,
1661G>C, 4180G>C
Cyp2D6*17xN
1023C>T, 1661G>C,
2850C>T, 4180G>C
Cyp2D6*36xN
100C>T, 1039C>T,
1661G>C, 4180G>C,
(gene conversion to
CYP2D7 in exon 9)
Cyp2D6*41xN
1661G>C, 2850C>T,
2988G>A, 4180G>C
Cyp2D6*41
,1661G>C,
2850C>T,
2988G>A,
4180G>C
Cyp2D6*40
1023C>T, 1661G>C,
1863ins(TTTCGCCCC)2,
2850C>T, 4180G>C
3
Incidence of Poor Metabolizer Phenotype: 10 percent of Caucasians and Hispanics, 2 percent
of African Americans, and 1 percent of Asians.
Clinical Sensitivity: Greater than 95 percent of deleterious CYP2D6 variants are detected in
Caucasians; sensitivity is unknown in other ethnicities.
Methodology: multiplex polymerase chain reaction (PCR) followed by hybridization to a
microarray.
Analytical sensitivity**: 99% (95% CI 90%-100% when compared against referent method).
Analytical specificity**: 100% (95% CI 94%-100% when compared against referent method).
Limitations: Only the targeted CYP2D6 variants will be detected. Mutations or variants in
other genes will not be detected. Rare diagnostic errors can occur due to primer site mutations.
Mutation detection is not a substitute for therapeutic drug monitoring. Non-genetic factors may
also affect drug metabolism. These results should be interpreted in light of clinical and familial
data.
* FDA-clearance of a particular assay may dictate the phenotype.
**Analytical sensitivity and specificity will be laboratory specific based on internal validation
data.
4
The Laboratory
1111 Laboratory Avenue
Nowhere, State 00839
(555) 920-3333
www.______.com
Patient Name:
ID number:
DOB:
Gender:
Ordering Physician:
Date of Report:
Jane D.
057398468
04/05/2007
Female
Dr. Good
June 15, 2010
Patient and Family Information
Race/Ethnicity:
Family History:
Personal history:
Concurrent Medications:
Test Performed:
CYP2D6
Indication for testing: Predictive response to tamoxifen
Specimen Type:
Blood
Result:
Interpretation:
*4/*4
Consistent with a Poor Metabolizer Phenotype.
Two copies of non-functional alleles were detected, consistent with a poor metabolizer phenotype. This
individual’s ability to metabolize Tamoxifen is predicted to be markedly reduced, rendering tamoxifen therapy less
effective. She is also at increased risk for drug-induced side effects due to diminished drug metabolism for other
drugs metabolized by CYP2D6.
Reference: Ingelman-Sundberg M, Daly AK, Nebert DW, Eds. 2009. Available in:
http://www.imm.ki.se/CYPalleles.
Guidance:


Alternative therapies, such as aromatase inhibitors, could be considered.
Consultation with a clinical pharmacy professional to discuss drug and dose selection is
recommended.


Additional information regarding this test is available from the laboratory (phone number)
Increased risk of drug-induced side effects; drug therapies should be closely monitored
This report was reviewed and approved by:
_____________________
__________
John Doe, M.D., Ph.D.
Director, The Molecular Laboratory
Date
5
The Laboratory
1111 Laboratory Avenue
Nowhere, State 00839
(555) 920-3333
www.______.com
Patient Name:
ID number:
DOB:
Gender:
Ordering Physician:
Date of Report:
Jane D.
057398468
04/05/2007
Female
Dr. Good
June 15, 2010
Patient and Family Information
Race/Ethnicity:
Family History:
Personal history:
Concurrent Medications:
Test Performed:
CYP2D6
Indication for testing: Predictive response to tamoxifen
Specimen Type:
Blood
Result:
Duplication: No Other Mutations Detected
Interpretation: Consistent with an Ultra-Rapid Metabolizer Phenotype.
More than two copies of the cytochrome P450 2D6 gene were detected. No other mutations were detected. This
result is consistent with the duplication of a functional allele predicting an ultra-rapid metabolizer phenotype and
increased Tamoxifen metabolism.
Drug metabolism may be affected by non-genetic factors. For example, co-administration of drugs that inhibit
CYP2D6 activity (e.g. some antidepressants) could impair or prevent metabolism of drugs metabolized by CYP2D6
(e.g. tamoxifen).
This result does not rule out the presence of other mutations within the cytochrome P450 family or other genetic
changes that can affect drug metabolism. It is possible that the individual has a rare variant in the CYP2D6 gene
that is not examined by this assay.
Reference: Ingelman-Sundberg M, Daly AK, Nebert DW, Eds. 2009. Available in:
http://www.imm.ki.se/CYPalleles.
Guidance:



This individual may require decreased dosage of Tamoxifen to obtain therapeutic response.
Treating with drugs that inhibit CYP2D6 metabolism may be effective.
Consultation with a clinical pharmacy professional to discuss drug and dose selection is
recommended.

Additional information regarding this test is available from the laboratory (phone number)
This report was reviewed and approved by:
_____________________
__________
John Doe, M.D., Ph.D.
Date
Director, The Molecular Laboratory
6
The Laboratory
1111 Laboratory Avenue
Nowhere, State 00839
(555) 920-3333
www.______.com
Patient Name:
ID number:
DOB:
Gender:
Ordering Physician:
Date of Report:
Jane D.
057398468
04/05/2007
Female
Dr. Good
June 15, 2010
Patient and Family Information
Race/Ethnicity:
Family History:
Personal history:
Concurrent Medications:
Test Performed:
CYP2D6
Indication for testing: Predictive response to tamoxifen
Specimen Type:
Blood
Result:
*2/*4xN
Interpretation: Consistent with an Extensive (Normal)-to-Intermediate* Phenotype.
One non-functional allele and one functional allele were detected in the cytochrome P450 2D6 gene, consistent with
normal-to-intermediate CYP2D6 activity. Some reduction in Tamoxifen metabolism is possible.
Drug metabolism may be affected by non-genetic factors. For example, co-administration of drugs that inhibit
CYP2D6 activity (e.g. some antidepressants) could impair or prevent metabolism of drugs metabolized by CYP2D6
(e.g. tamoxifen).
This result does not rule out the presence of other mutations within the cytochrome P450 family or other genetic
changes that can affect drug metabolism. It is possible that the individual has a rare variant in the CYP2D6 gene
that is not examined by this assay.
Reference: Ingelman-Sundberg M, Daly AK, Nebert DW, Eds. 2009. Available in:
http://www.imm.ki.se/CYPalleles.
Guidance:


This individual may require a higher than normal drug dosage for optimal therapeutic response.
Patient should avoid CYP2D6 inhibitors, such as Fluoxetine, Paroxetine, Quinidine, or Bupropion.
A list of drugs is available at http://medicine.iupui.edu/clinpharm/ddis/table.asp

Multiple drug therapies should be monitored closely.

Consultation with a clinical pharmacy professional to discuss drug and dose selection is
recommended.

Additional information regarding this test is available from the laboratory (phone number)
This report was reviewed and approved by:
________________
__________
John Doe, M.D., Ph.D.
Date
Director, The Molecular Laboratory
7
The Laboratory
1111 Laboratory Avenue
Nowhere, State 00839
(555) 920-3333
www.______.com
Patient Name:
ID number:
DOB:
Gender:
Ordering Physician:
Date of Report:
Test Performed:
Indication for testing:
Specimen Type:
Jane D.
057398468
Patient and Family Information
04/05/2007
Race/Ethnicity:
Female
Family History:
Dr. Good
Personal history:
June 15, 2010
Concurrent medications:
CYP2D6
Predictive response to tamoxifen
Blood
Result:
*10/*4
Interpretation: Consistent with an Intermediate-to-Poor Phenotype.
One non-functional allele and one decreased function allele were detected in the cytochrome P450 2D6 gene,
consistent with impaired CYP2D6 metabolism (intermediate-to-poor metabolizer). This individual may have
decreased Tamoxifen metabolism and at an increased risk for drug-induced side effects due to diminished drug
metabolism for other drugs metabolized by CYP2D6.
Drug metabolism may be affected by non-genetic factors. For example, co-administration of drugs that inhibit
CYP2D6 activity (e.g. some antidepressants) could impair or prevent metabolism of drugs metabolized by CYP2D6
(e.g. tamoxifen).
This result does not rule out the presence of other mutations within the cytochrome P450 family or other genetic
changes that can affect drug metabolism. It is possible that the individual has a rare variant in the CYP2D6 gene
that is not examined by this assay.
Reference: Ingelman-Sundberg M, Daly AK, Nebert DW, Eds. 2009. Available in:
http://www.imm.ki.se/CYPalleles.
Guidance:


This individual may require a higher than normal drug dosage for optimal therapeutic response.
Patient should avoid CYP2D6 inhibitors, such as Fluoxetine, Paroxetine, Quinidine, or Bupropion.
A list of drugs is available at http://medicine.iupui.edu/clinpharm/ddis/table.asp

Multiple drug therapies should be monitored closely.

Consultation with a clinical pharmacy professional to discuss drug and dose selection is
recommended.

Additional information regarding this test is available from the laboratory (phone number)
This report was reviewed and approved by:
_____________________
__________
John Doe, M.D., Ph.D.
Director, The Molecular Laboratory
Date
8
The Laboratory
1111 Laboratory Avenue
Nowhere, State 00839
(555) 920-3333
www.______.com
Patient Name:
ID number:
DOB:
Gender:
Ordering Physician:
Date of Report:
Test Performed:
Indication for testing:
Specimen Type:
Jane D.
057398468
Patient and Family Information
04/05/2007
Race/Ethnicity:
Female
Family History:
Dr. Good
Personal history:
June 15, 2010
Concurrent medications:
CYP2D6
Predictive response to tamoxifen
Blood
Result:
*10XN/*41
Interpretation: Consistent with Intermediate-to-Extensive Metabolizer Phenotype.
More than two copies of the cytochrome P450 2D6 gene were detected, including two decreased function alleles.
Duplication of decreased function alleles may enhance overall enzyme function leading to normal CYP2D6 activity
and normal Tamoxifen metabolism.
Drug metabolism may be affected by non-genetic factors. For example, co-administration of drugs that inhibit
CYP2D6 activity (e.g. some antidepressants) could impair or prevent metabolism of drugs metabolized by CYP2D6
(e.g. tamoxifen).
This result does not rule out the presence of other mutations within the cytochrome P450 family or other genetic
changes that can affect drug metabolism. It is possible that the individual has a rare variant in the CYP2D6 gene
that is not examined by this assay.
Reference: Ingelman-Sundberg M, Daly AK, Nebert DW, Eds. 2009. Available in:
http://www.imm.ki.se/CYPalleles.
Guidance:


This individual may require a higher than normal drug dosage for optimal therapeutic response.
Patient should avoid CYP2D6 inhibitors, such as Fluoxetine, Paroxetine, Quinidine, or Bupropion.
A list of drugs is available at http://medicine.iupui.edu/clinpharm/ddis/table.asp

Multiple drug therapies should be monitored closely.

Consultation with a clinical pharmacy professional to discuss drug and dose selection is
recommended.

Additional information regarding this test is available from the laboratory (phone number)
This report was reviewed and approved by:
_________________
__________
John Doe, M.D., Ph.D.
Date
Director, The Molecular Laboratory
9
The Laboratory
1111 Laboratory Avenue
Nowhere, State 00839
(555) 920-3333
www.______.com
Patient Name:
ID number:
DOB:
Gender:
Ordering Physician:
Date of Report:
Test Performed:
Indication for testing:
Specimen Type:
Jane D.
057398468
Patient and Family Information
04/05/2007
Race/Ethnicity:
Female
Family History:
Dr. Good
Personal history:
June 15, 2010
Concurrent medications:
CYP2D6
Predictive response to tamoxifen
Blood
Result:
*41/Interpretation: Consistent with an Extensive Metabolizer Phenotype.
One decreased function allele was detected in the cytochrome P450 2D6 gene. Because a functional allele may
compensate for the presence of a decreased function allele, this result is consistent with normal CYP2D6 activity.
Drug metabolism may be affected by non-genetic factors. For example, co-administration of drugs that inhibit
CYP2D6 activity (e.g. some antidepressants) could impair or prevent metabolism of drugs metabolized by CYP2D6
(e.g. tamoxifen).
This result does not rule out the presence of other mutations within the cytochrome P450 family or other genetic
changes that can affect drug metabolism. It is possible that the individual has a rare variant in the CYP2D6 gene
that is not examined by this assay.
Reference: Ingelman-Sundberg M, Daly AK, Nebert DW, Eds. 2009. Available in:
http://www.imm.ki.se/CYPalleles.
Guidance:

With an extensive metabolizer phenotype, Tamoxifen treatment can follow standard dosing
procedures.

Patient should avoid CYP2D6 inhibitors, such as Fluoxetine, Paroxetine, Quinidine, or Bupropion.
A list of drugs is available at http://medicine.iupui.edu/clinpharm/ddis/table.asp.

Additional information regarding this test is available from the laboratory (phone number)
This report was reviewed and approved by:
____________________
__________
John Doe, M.D., Ph.D.
Date
Director, The Molecular Laboratory
10