The Sulston Project

Evaluating the Effect(S) of Supreme Court Case Decisions Mayo Collaborative Services V Prometheus Laboratories (2012) and Association for Molecular Pathology V. Myriad Genetics (2013) on Hereditary Cancer Genetic Testing Practices & Access

By: Kara Hapke

Hypothesis:

Following the Supreme Court case decisions of Mayo Collaborative Services v Prometheus Laboratories (2012) and Association for Molecular Pathology v. Myriad Genetics (2013), an increase in the number of genetic testing companies offering BRCA1, BRCA2, PALB2, MUTYH, and RAD51C testing, either individually or as part of a cancer panel, will be observed.

Purpose:

Following the Supreme Court case decisions of Mayo Collaborative Services v Prometheus Laboratories (2012) and Association for Molecular Pathology v. Myriad Genetics (2013), the purpose of this case study is to determine (if applicable) a potential “increase”, “decrease”, or “no change” in the:

Frequency of patients’ receiving genetic testing for BRCA1, BRCA2, PALB2, MUTYH, and RAD51C
- Accounting for “Angelina Jolie effect”
Number of companies offering genetic testing for BRCA1, BRCA2, PALB2, MUTYH, and RAD51C
Number of genetic testing companies newly formed
Cost of genetic testing for BRCA1, BRCA2, PALB2, MUTYH, and RAD51C

Methods:

NCBI ClinVar contribution data[1] was utilized to identify laboratories conducting genetic testing for BRCA1, BRCA2, PALB2, MUTYH, and RAD51C genetic variations (see: Tables 2-6). Laboratories not contributing to ClinVar were excluded for potential interview, with the exception of Myriad Genetics. Based on the numerical quantity of their ClinVar contribution(s), genetic testing laboratories were classified into three categories: significant contributor, moderate contributor, and minor contributor (see: Table 1). The laboratories were classified into the aforementioned three groups to ensure a thorough and evenly distributed evaluation for anticipated interview selection.

Table 1: Genetic Testing Laboratory Classification based on ClinVar Submission(s)

‘Significant’ Contributor:	>1000 Variants AND >250 are Pathogenic
‘Moderate’ Contributor:	>500 Variants AND >125 are Pathogenic
‘Minor’ Contributor:	>100 Variants AND >10 are Pathogenic*
*Minimum ClinVar Contribution for Interview Invitation: >100 Variants AND >10 are pathogenic

Source: https://www.ncbi.nlm.nih.gov/clinvar/

Table 2: ClinVar Submitters for BRCA1 Variants

Submitter:	Classification:	Contribution (Total):	Contribution (Pathogenic):
Invitae	Significant	2367	517
Ambry Genetics	Significant	2259	574
Color	Significant	1747	285
Breast Cancer Information Core (BIC)	Significant	1739	846
GeneDx	Significant	1425	429
SCRP	Moderate	896	443
Lab Corp	Moderate	799	186
Quest Diagnostics	Moderate	647	265
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Moderate	526	462
Dept. of Pathology and Laboratory Medicine, Sinai Health System	Minor	381	130
GeneKor MSA	Minor	143	98
Mendelics	Minor	115	52
Michigan Medical Genetics Laboratories, Univ of Michigan	Minor	114	42
Dept. of Medical Genetics, Oslo Univ. Hosp.	Minor	111	98
ARUP Laboratories, Molecular Genetics and Genomics	Minor	105	22
Prevention Genetics	Minor	102	12
Diagnostic Laboratory, Dept. of Genetics, University Medical Center Groningen	Minor	102	65

Source: https://www.ncbi.nlm.nih.gov/clinvar/

Table 3: ClinVar Submitters for BRCA2 Variants

Submitter:	Classification:	Contribution (Total):	Contribution (Pathogenic):
Invitae	Significant	4334	860
Ambry Genetics	Significant	4025	834
Color	Significant	2820	466
GeneDx	Significant	2348	628
Breast Cancer Information Core (BIC)	Significant	1966	795
Lab Corp	Significant	1364	270
Quest Diagnostics	Significant	1064	347
Dept. of Pathology and Laboratory Medicine, Sinai Health System	Moderate	598	153
Research Molecular Genetics Laboratory, Women's College Hopsital, University of Toronto	Minor	497	451
ARUP Laboratories, Molecular Genetics and Genomics	Minor	238	53
Michigan Medical Genetics Laboratories, Univ of Michigan	Minor	207	48
Mendelics	Minor	202	58
DNA and Cytogenetics Diagnostics Unit, Erasmus Medical Center	Minor	200	67
Prevention Genetics	Minor	182	15
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	Minor	158	20
CHEO Genetics Diagnostics Laboratory, Children's Hospital of Eastern Ontario	Minor	150	34
Genome Diagnostics Laboratory, University Medical Center Utrecht	Minor	144	24
GeneKor MSA	Minor	144	88
Diagnostic Laboratory, Dept. of Genetics, University Medical Center Groningen	Minor	141	77
Lab for Molecular Medicine, Partners HealthCare Personalized Medicine	Minor	137	74
Foulkes Center Genetics LDI, Lady Davis Institute for Medical Research	Minor	103	44

Source: https://www.ncbi.nlm.nih.gov/clinvar/

Table 4: ClinVar Submitters for PALB2 Variants

Submitter:	Classification:	Contribution (Total):	Contribution (Pathogenic):
Invitae	Significant	1548	272
Ambry Genetics	Significant	1187	221
Color	Moderate	891	103
GeneDx	Moderate	727	109
PALB2 database	Minor	215	43
Lab Corp	Minor	163	11
Quest Diagnostics	Minor	125	32

Source: https://www.ncbi.nlm.nih.gov/clinvar/

Table 5: ClinVar Submitters for MUTYH Variants

Submitter:	Classification:	Contribution (Total):	Contribution (Pathogenic):
Invitae	Minor	641	73
Ambry Genetics	Minor	549	49
Color	Minor	481	33
GeneDx	Minor	273	41

Source: https://www.ncbi.nlm.nih.gov/clinvar/

Table 6: ClinVar Submitters for RAD51C Variants

Submitter:	Classification:	Contribution (Total):	Contribution (Pathogenic):
Hereditary cancer-predisposing syndrome*	Minor	538	38
Fanconi anemia, complementation group O*	Minor	497	61
*Unknown Contributor

Source: https://www.ncbi.nlm.nih.gov/clinvar/

Table 7: ClinVar Submitters (within the U.S.) Selected for Interview Invitation & Associated Genetic Testing Offerings

Invitae	Ambry	Color	GeneDx	Lab Corp	Quest	ARUP	Myriad
BRCA1	BRCA1	BRCA1	BRCA1	BRCA1	BRCA1	BRCA1	-
BRCA2	BRCA2	BRCA2	BRCA2	BRCA2	BRCA2	BRCA2	-
PALB2	PALB2	PALB2	PALB2	PALB2	PALB2	-	-
MUTYH	MUTYH	MUTYH	MUTYH	-	-	-	-

Source: https://www.ncbi.nlm.nih.gov/clinvar/

Table 8: ClinVar Submitters (within the U.S.) Interviewed

Submitter:

DC-I (Diagnostic Company I)*

DC-II (Diagnostic Company II)*

*Interviewee/Organization Name Redacted for Privacy

Table 8: Genetic Testing Experts Interviewed

Interviewee:

GTE-I (Genetic Testing Expert I)*

GTE-II (Genetic Testing Expert II)*

*Interviewee/Organization Name Redacted for Privacy

Table 9: Qualitative Interview Questions

Question 1	Do you offer BRCA1, BRCA2, PALB2, MUTYH, and/or RAD51C testing? If no, do you offer these tests for research? If yes, when did you start offering these tests?
Question 2	When did you start offering cancer multi-gene panel testing? Which genes are included? How do you decide which genes to include? If you were to add a gene to your cancel panel, how much would this cost you? How long would it take to set up?
Question 3	Did you exclude BRCA1/2 from cancer gene panels before the Supreme Court decision in Myriad in June 2013? If yes, did you include BRCA1/2 after June ’13?
Question 4	Did the 2012 Supreme Court decision in Mayo v Prometheus change your genetic testing practices? If yes, how?
Question 5	Did the patent situation affect data availability, in your view?
Question 6	What role do use of databases that are freely available (e.g., ClinVar, gnomAD and LOVD) play in clinical interpretation of the results from genetic tests for inherited cancer risk? What about subscription-based databases (e.g., BRCA Share when it existed, or the Human Gene Mutation Database or Universal Mutation Database or others)?
Question 7	What is your opinion on sharing data from the results of your tests with public databases like ClinVar, gnomAD, and LOVD? What data do you contribute to public databases? What about VUS? What data do not get shared with public databases? What data do you regard as 'open', 'private' or 'proprietary'?
Question 8	How do you arrive at your interpretation of a variant? If you’ve encountered a variant before, but can’t interpret it, what is do you do? How do you handle an uncertainty/discrepancy in your interpretation?
Question 9	What do you think might happen if either individual variants, or associations between variants and diseases/conditions, were to become patent-eligible again? Would you change anything you do at your lab? Would you feel obligated to obtain “defensive” variant-based or gene-association-based patents to forestall patent infringement liability?
Question 10	Is there anyone else whom you believe we should interview?

Discussion:

TBD. Case study currently in progress. See “Note” below.

Conclusion:

TBD. Case study currently in progress. See “Note” below.

Important Note:

Due to the overwhelming effects SARS-CoV-2 has had on diagnostic testing laboratories, this qualitative case study has been temporarily halted as of March ‘20. As a result, the present sample size of qualitative interviews with both genetic testing laboratories and genetic testing experts is very small, respectively, is n=2 and n=2. The qualitative interviews will resume once the impact of SARS-CoV-2 has lessened, which is expected to be in Fall ’20.

References

ClinVar. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/clinvar/ (accessed June 3, 2020).
MAYO COLLABORATIVE SERVICES, DBA MAYO MEDICAL LABORATORIES, ET AL. v. PROMETHEUS LABORATORIES, INC. US Supreme Court 2012. https://www.supremecourt.gov/opinions/11pdf/10-1150.pdf (accessed June 3, 2020).
ASSOCIATION FOR MOLECULAR PATHOLOGY ET AL. v. MYRIAD GENETICS, INC., ET AL. . US Supreme Court 2013. https://www.supremecourt.gov/opinions/12pdf/12-398_1b7d.pdf (accessed June 3, 2020).