ACMG Clinically Relevant Mutations for Cancer

Creating a list of clinically relevant pathogenic variants for cancer

The majority of this post is taken from the following paper, written by Miller et al., 2022

Below, I created a list of clinically relevant mutations for cancer from this paper. The majority of the below are autosomal dominant:

1. APC - FAP
2. RET - Thyroid cancer, MEN type 2
3. BRCA1 - breast cancer
4. BRCA2 - breast cancer
5. PALB2 - breast cancer
6. SDHD - Hereditary paraganglioma-pheochromocytoma syndrome
7. SDHAF2 - “
8. SDHC- “
9. SDHB- “
10. MAX- “
11. TMEM127 - “
12. BMPR1A - Juvenile polyposis syndrome
13. SMAD4 - Juvenile polyposis syndrome
14. TP53- Li Fraumeni
15. MLH1 - Lynch syndrome (HNPCC)
16. MSH2 - Lynch syndrome (HNPCC)
17. MSH6 - Lynch syndrome (HNPCC)
18. PMS2 - Lynch syndrome (HNPCC)
19. MEN1 - Multiple endocrine neoplasia type 1
20. MUTYH - MUTYH (MYH)-associated polyposis
21. NF2 - Neurofibromatosis type 2
22. STK11 - Peutz-Jeghers syndrome
23. PTEN - PTEN hamartoma tumor syndrome
24. RB1 - Retinoblastoma
25. TSC1 - Tuberous sclerosis complex
26. TSC2 - Tuberous sclerosis complex
27. VHL - von Hippel-Lindau syndrome
28. WT1 - Wilm Tumor

It sounds like Dr. Maxwell is interested in investigating all of the above, including several more genes: BRIP1, RAD51C, RAD51D, HOXB13, ATM and CHEK2.

Some other genes are noted in some parts of the paper, which were not recommended for clinical consideration in cancer risk:

• BRIP1, RAD51C, and RAD51D are related to ovarian cancer and were not yet added due to “penetrance concerns and lack of effective surveillance modalities for ovarian cancer also a consideration”
• HOXB13, ATM, and CHEK are not mentioned

In another paper by Dr. Maxwell seen here, she includes “medically relevant genes” to a much greater degree. She includes a list of 135 genes by Rahman, clinically relevant genes by the institute for cancer research (unable to find source), and a gene list created by Stadler et al.. Overall, this list includes ~190 genes, in comparison to the ~30 listed above.

In summary, I can immediately appreciate it’s challenging to create a list of the correct length with genes relevant to oncology. It should include genes that cover broad types of cancer and are known to be implicated. However, it should limit including less known genes that only have weaker associations. I believe further discussion is needed to create a concrete list of pathogenic and likely pathogenic variants before proceeding to data analysis.