Cancer Susceptibility Genes

DRAFT RESOURCE FOR REVIEW

Genomic tumor testing performed for treatment decision-making may identify variants that are also present in the germline, conferring hereditary cancer risk to the patient and relatives. Additional germline testing may be indicated to provide the most accurate and complete information about potential germline variants, particularly when somatic only testing was performed.

The purpose of this resource is to list cancer susceptibility genes that have published medical management recommendations and/or strong evidence supporting the association of the gene with cancer risk. The clinician should consider additional factors in the decision to refer for germline testing: the patient’s tumor type, age at diagnosis, personal and family history, variant allele fraction, test type (somatic only vs. paired germline/somatic) and the utility of germline testing for the specific individual. This list is not exhaustive and is likely to change over time. 

Cancer susceptibility genes that warrant referral for germline testing

Bold genes: Germline testing is generally recommended.
Other genes: Consider germline testing based on patient age at diagnosis, tumor type, family history, and other factors.

APC

MEN1

SDHA

ATM

MLH1

SDHAF2

BAP1

MSH2

SDHB

BARD1

MSH6

SDHC

BMPR1A

MUTYH*

SDHD

BRCA1

NF1

SMAD4

BRCA2

NF2

SMARCA4

BRIP1

PALB2

STK11

CDH1

PMS2

TMEM127

CDKN2A

POLE

TP53

CHEK2

PTEN

TSC1

DICER1

RAD51C

TSC2

FH

RAD51D

VHL

FLCN

RB1

WT1

MAX

RET

 

* germline testing only recommended when two pathogenic/likely pathogenic variants are present in the gene

Learn more

For further guidance on when to order germline testing after genomic tumor testing, see:

Indications for Germline Testing for Cancer Patients. This tool provides an overview about the process and questions to help determine the appropriateness of germline testing.

Indications for Germline Testing after Genomic Tumor Testing (CME/CNE).[link to be inserted] Practice identifying patients for germline referral based on test type, family history, and gene variant or biomarker. 

References 

DeLeonardis K, Hogan L, Cannistra SA, Rangachari D & Tung NJ. (2019). When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing? Journal of Oncology Practice, 15(9):465-473.

Fiala EM, Jayakumaran G, Mauguen A et al. (2021). Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors. Nature Cancer, 2:357-365.

Mandelker D, Zhang L, Kemel Y et al. (2017). Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA, 318(9):825-835.

Mandelker D, Donoghue M, Talukdar S, et al. (2019) Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group. Annals of Oncology, 30(8):1221-1231.

Miller DT, Lee K, Chung WK et al. (2021). ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine, 23(8):1381-1390.

Schrader KA, Cheng DT, Joseph V et al. (2016). Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA. JAMA Oncology, 2(1):104-11.

About 

This resource was developed as part of Precision Oncology Online Education and the Maine Cancer Genomics Initiative (MCGI) and is supported by The Harold Alfond Foundation, Maine Cancer Foundation, and The Jackson Laboratory. 

Developed October 2021

Disclaimer

All information in Precision Oncology Online Education is provided for educational purposes only. This information is not a substitute for clinical guidance or the consultation of a medical professional. Always seek the advice of a qualified health professional with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in Precision Oncology Online Education. Reliance on any information in Precision Oncology Online Education is solely at your own risk. The Jackson Laboratory does not endorse or recommend any specific procedures, tests, products, services, health professionals or other information that may be found in Precision Oncology Online Education.