# Germline variants in CDKN2A wild‐type melanoma prone families

## TL;DR

This study finds that some melanoma-prone families without CDKN2A mutations have pathogenic variants in other genes, suggesting new genetic causes for inherited melanoma.

## Contribution

The study identifies novel germline pathogenic variants in genes not typically associated with melanoma in CDKN2A wild-type families.

## Key findings

- Six index individuals had pathogenic variants in genes like BRCA2, MRE11, ATM, MSH2, CHEK2, and AR.
- A high frequency of XPC L48F variant was found in melanoma-prone families compared to healthy populations.
- Rare xeroderma pigmentosum-related and MC1R variants are enriched in CDKN2A wild-type melanoma families.

## Abstract

Germline pathogenic variants in CDKN2A are well established as an underlying cause of familial malignant melanoma. While pathogenic variants in other genes have also been linked to melanoma, most familial cases remain unexplained. We assessed pathogenic germline variants in 360 cancer‐related genes in 56 Norwegian melanoma‐prone families. The index cases were selected based on familial history of melanoma and/or multiple primary melanomas, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants in BRCA2, MRE11, ATM, MSH2, CHEK2, and AR. One family member with melanoma (not index case) carried a pathogenic variant in MAP3K6. In addition, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance in xeroderma pigmentosum‐related genes. In particular, XPC

L48F
was found in 8 indexes; thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (0.02–0.03; P‐values from 0.007 to 0.014). In conclusion, we found that several melanoma‐prone families have pathogenic variants in genes not usually linked to melanoma.

Among melanoma‐prone families, wild‐type for CDKN2A and CDK4, some have pathogenic variants in genes not usually linked to melanoma. Furthermore, rare XP‐related variants and variants in MC1R are enriched in such families.