1. Susan Domchek, MD University of Pennsylvania
Germline testing
Susan Domchek, MD
University of Pennsylvania

2. Key issues
Do oncologists underestimate the power of germline genetics?
Predictive testing can prevent disease – in our patients and their family members
It is important and valuable in its own right
Germline findings can have therapeutic implications on their own
Many of our patients should have already had germline testing before they developed cancer
What happens with the data subtraction? Where do these data go?

3. Germline testing is standard of care
Many diseases in which all patients should be offered germline testing
Adrenocortical
Pheochromocytoma
Paraganglioma
Ovarian cancer
Triple negative breast cancer <60
Diffuse gastric cancer <40
Medullary thyroid cancer
Etc etc
What happens with the data subtraction? Where do these data go?
Hampell Gen Med et al 2015

4. Case 1: Germline testing can prevent disease
BRCA1 C61G
This woman would have been aided much more by predictive germline testing and risk reducing salpingo-oophorectomy than somatic sequencing of the tumor she developed
Will help her family members
GINA

5. Key issues
There are several ways to do tumor testing: do patients and providers understand germline implications of each method?
Paired germline/somatic vs somatic with germline subtracted vs somatic only
Understand strengths and weaknesses
Develop strategies so that data can be used
Appropriate consent
What happens with the data subtraction? Where do these data go?

6. Case 2: Does anyone understand what we are doing?

10. Technical aspects of germline sequencing
Rationale for germline sequencing are different and sensitivity for mutations is not necessarily the same
Identification of cancer susceptibility variants vs. comparison to a tumor sequence
Sensitivity of deletion/duplication? Uniform coverage?
Current standard remains to do germline testing if indicated regardless of somatic results

11. Key issues
Reporting:
Differential level of variant review and annotation for germline and somatic
Testing is done for different reasons – and may have different thresholds
Not everything needs to be further evaluated in the germline (VUS/benign in ClinVar)
Clarification of reporting
Founder mutations
Allelic frequency?
Beyond cancer related genes?
What happens with the data subtraction? Where do these data go?

12. Case 3: Multiple reporting confusions
Oncologist at Penn had received germline and somatic testing reports and “it is very weird but the patient has different mutations in germline and tumor”
BRCA1 C61G, c.181T>G: They are the same
Patient – very concerned because her uncle has a different germline mutation than she does – does she need to be retested?
BRCA1 187delAG (also known as BRCA1 185delAG and c.68_69delAG)
Common Ashkenazi Jewish founder mutation

15. Case 4: Variants of Uncertain Significance
Not infrequent that findings on somatic reports are “unimportant” in ClinVar
VUS: When found in the germline – we do not act on these, management is based on family history
GENIE and other initiatives
May be particularly important in loss of function
For alternations that on the germline side would be VUS at best – this may “dilute” the study, as we may not expect responses

16. Key issues
Somatic only – the de facto standard in the community at this time
What results should trigger rapid and low barrier referral for germline testing? Why does this matter?
Extending beyond the traditional model - cancer community has create new models
What happens with the data subtraction? Where do these data go?

17. Case 5: Why do germline testing once we have somatic results?
Somatic sequencing in the mother’s ovarian tumor:
BRCA2 6014_6017delATAG
Testing in the two daughters is uninformative without knowing if the mutation is germline in the mother
We were able to obtain a sample while proband was on hospice: no germline mutation was detected
TC model includes negative genetic testing in proband and her sister
Irish/English, no AJ

18. Best practice list: Somatic sequencing findings with consideration for gemline testing
Tumors with a pathogenic or likely pathogenic BRCA1, BRCA2, MLH1, MSH2, or MSH6 mutations
Pathogenic variants in BRIP1, PALB2, RAD51C, RAD51D
Founder mutations (which will be specified in report)
TP53 R337H; ATM V2424G;
APC I1307K; CHEK2 1100delC, I157T, S428F will have explanatory text (as moderate prevalence founder/common mutations)
Pathogenic variants in genes for which your patient appears to have an associated clinical phenotype (See checklist )
Patients whose personal or family history is suggestive of a hereditary cancer syndrome should be referred regardless of somatic testing results
D Clark, K Maxwell, K Nathanson, S Domchek, J Morrissette

19. Considerations
Embrace the germline: risk prediction and prevention for patients and family members – as well as targeted therapy
Consent, disclosure, and data usage
Clarity of testing and reporting for providers and patients
Novel models for consent and information dissemination

20. Suggestions from the clinical oncologist
Encourage use of germline testing early in disease in appropriate candidates
Clarify reporting: Type of testing and reporting of results
Clearly identify type of testing
Clearly identify founder mutations
Develop consistent reporting across germline and somatic sequencing
Develop a best practice list of which somatic results should be promptly referred to germline testing

21. Recommendations from the germline panel
Encourage analysis of the germline
Improve annotation and reporting
Evolve paradigms for consent and return of results
Provide guidance for community oncologist for inferences of germline in somatic testing