Introduction: Ataxia-Telangiectasia Mutated (ATM) is a cancer predisposition gene; carriers of germline pathogenic variants have an increased risk of developing malignancies, including breast, prostate, pancreatic, and ovarian cancer. Most ATM variants are of uncertain significance. Findings from genome-wide association studies (GWAS) suggest that ATM may be a low-risk melanoma susceptibility locus. Case Report: We report the case of a Hispanic family whose members who have presented cutaneous melanoma have been found to be carriers for the ATM pathogenic variant c.3747-1G>C (rs730881364), one of whom was diagnosed at 24 years old. Discussion: We describe for the first time the possible clinical association between ATM (c.3747-1G>C) and familial melanoma. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site, assuming a variant that entails loss of functionality that is probably pathogenic and related to oncogenesis. However, we cannot exclude that cutaneous melanoma in both members and at an early age is the result of chance, environmental interaction, other uncontrolled external factors, or the interaction of other genetic alterations other than the ATM variant described in this study.

Cutaneous melanoma (CM) is the type of skin cancer with the highest mortality, being the 6th cause of death from cancer in developed countries [1]. Its incidence varies depending on geographical location. The annual European incidence of malignant melanoma varies from 3 to 5/100,000 in Mediterranean countries to 12–35/100,000 in the Nordic countries, while it can reach more than 50/100,000 in Australia or New Zealand [2, 3]. Phenotypic and environmental factors, such as skin phototype, the presence of atypical nevi, exposure to sunlight, and sunburn, are known to increase the risk of CM. However, 5–12% of MC cases have a positive family history for this malignancy [2, 4, 5]. Even so, most of these cases with a family history are sporadic, and only 10% of them are classified as hereditary melanoma [1].

Ataxia-Telangiectasia Mutated (ATM) is a cancer predisposition gene, as heterozygous carriers of germline pathogenic variants of ATM are at increased risk of developing several types of malignancies, including breast cancer and prostate cancer [4]. Findings from genome-wide association studies (GWAS) suggest that ATM may be a low-risk melanoma susceptibility locus [4, 6‒9].

We report the case of a family whose members who have presented CM have been found to be carriers for the ATM variant c.3747-1G>C (rs730881364). To date, there has been no publication of this variant in direct relation to CM or other types of neoplasia. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000536105).

We present the case of a Hispanic woman with skin phototype 4, without personal medical history, no report of atypical moles, abusive sun exposure, or sunburns, diagnosed in 2015 with 65 years old of localised CM in the right leg treated by surgical excision with widened margins and sentinel lymph node biopsy that resulted negative. Her family history includes a mother who died probably due to a neoplasia in the head of the pancreas (without pathological confirmation), a son also Hispanic with skin phototype 4, no report of atypical moles, abusive sun exposure, or sunburns, diagnosed in 2005, with 24 years old, and localised CM in the left arm treated with surgery with widened margins. One of his brothers was diagnosed with ampulloma when he was 53 years old and CM 10 years later, when he was 63 years old. Due to his family record, the patient was referred to genetic counselling. A 23s panel sequencing (APC, ATM, BAP1, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53) was performed using genomic DNA isolated from whole blood from the patient.

Variants were classified following the guidelines of the American College of Medical Genetics and Genomics (ACMG). A board of molecular clinical geneticists evaluated each variant classified as pathogenic, likely pathogenic, or a variant of uncertain significance and decided which, if any, had to be reported. Identified variants were confirmed by Sanger sequencing. In cases of deletions or duplications, these are confirmed by the MLPA.

The proband tested positive for the ATM germline pathogenic variant (c.3747-1G>C) (rs730881364). Once this mutation was identified, it was tested in the first-degree relatives, resulting positive for ATM c.3747-1G>C; his son was diagnosed with CM at the age of 24. The brother diagnosed with CM when he was 68 years old refused genetic testing. The genetic tree is illustrated in Figure 1.

Fig. 1.

Genetic tree.

We report the presence of the pathogenic variant ATM c.3747-1G>C (rs730881364) in 2 first-degree relatives affected by CM, in one of the cases, at the age of 24 years old. Familial melanoma is genetically heterogeneous. To date, various genes have been implicated in the pathogenesis of this disease; however, less than half of families with a strong family history of melanoma (high-risk families) result positive for any mutation. Familial melanoma susceptibility genes are grouped for study into rare, high-penetrance genes and more common but low-penetrance genes [1, 5, 10].

According to the bibliography, among the genes with high penetrance, stand out CDKN2A, CDK4, BRCA1-associated protein-1 (BAP1) as genes related to the cell cycle and cell proliferation, and genes related to telomere maintenance and elongation such as POT1, ACD, TERT, and TERF2IP [1, 10‒12]. Moderate and low risk genes have a weak impact on melanoma susceptibility. Typically, families with these variants have between one and two cases of melanoma. But if a combination of low- to moderate-risk genes is inherited, more cases of CM could be present, with the risk being greater in those families that live in areas with increased UV radiation [11].

In 2009, the criteria for referring patients to genetic counselling for hereditary melanoma were defined: patients with 2 or 3 or >3 CM; families with 2, 3 or >3 1st and 2nd degree relatives affected by melanoma, including relatives with pancreatic cancer [11, 12]. A distinction is made between 2 or 3 cases of CM depending on the geographical region and UV radiation because in geographic areas with higher background rates of melanoma, there is greater likelihood of having multiple family members with melanoma or multiple primary melanomas caused by reasons other than a mutation. For moderate to high melanoma incident areas, individuals with 3 or more primary melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of melanoma and/or pancreatic cancer in aggregate among first- or second-degree relatives on the same side of the family are appropriate candidates for a genetic evaluation [10‒12]. In our case, Spain has a low incidence of CM compared to other northern European countries so the development of two or more melanomas in an individual or family would be referred for genetic counselling [2, 3, 5].

ATM gene is located in 11q22.3 and is responsible for the rare disorder ataxia-telangiectasia. Patients show various abnormalities, mainly in their responses to DNA damage, but also in other cellular processes. ATM acts specifically in the cellular response to ionising radiation and DNA double-stranded breaks [13]. ATM gene mutation is found in less than 1% of the general population, and association studies conducted with controls have shown that these alleles are characterised by a moderate risk (RR: 2–4) for hereditary cancer. Mutations in ATM incompletely cosegregate the disease, with an estimated 15% of mutation carriers in this gene developing cancer. The incomplete penetrance of ATM, as well as other moderate-risk genes, supports that they follow a polygenic model of cancer susceptibility [14]. The ambry genetics tool reports ATM as the 4th most common gene in any cancer with 1.23% mutation probability in 78,636 probands [15]. In melanoma, it is also the 4th most common gene with 1.26% probability in 2,542 probands [15]. As described before, heterozygous carriers of germline pathogenic variants of ATM are at increased risk of developing several types of malignancies, including breast cancer and prostate cancer [4].

ATM is an intermediate-risk breast cancer susceptibility gene that has been implicated in melanoma susceptibility [16‒19], but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified [4, 8, 18]. Dalmasso B et al. conducted a multicenter study among the GenoMEL and MelaNostrum melanoma genetics consortia to further investigate the impact of ATM on the risk of developing melanoma. From centers across 22 sites in Europe, the USA, and Australia, this is the largest multicenter melanoma retrospective cohort investigated for ATM germline variants [18]. They considered all nonsense, frameshift, splice acceptor, and splice donor ATM variants found in either our study cohort or the NFE gnomAD cohort, and they were considered LOF (loss of function). In their statistical analysis, they support the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate risk [18].

The c.3747-1G>C variant is located in the canonical acceptor splice site of intron 25, and it is predicted to disrupt the canonical acceptor and activate a cryptic acceptor in position c.3760. The use of this new acceptor site would produce a shorter exon 26 and the disruption of the reading frame, triggering nonsense-mediated decay [20]. This variant was found in one ataxia-telangiectasia proband. Assays performed with lymphoblastoid cell lines of an ataxia-telangiectasia patient showed that the ATM protein was absent and there was a clearly increased radiosensitivity [21]. Splicing analysis in carrier RNA shows the loss of the first 13 nucleotides of exon 26, leading to the predicted frameshift and NDM. In a work carried out by Osorio A and Llorts G presented as an oral communication, the mutation in ATM c.3747-1G>C changes the open reading frame, and a stop codon appears 9 amino acids downstream [22]. Therefore, this variant meets the criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group [20, 23].

In our case, a mutational panel was carried out, including both mutations in genes of high and moderate-low penetrance, as well as other genes involved in the pathogenesis of other neoplasms and that have been related to CM in the literature, as occurs with BRCA 1/2, TP53, PALB2, MLH1, MSH2, MSH6, PMS2, CDH1, CHEK2, NF1, PTEN, STK11, TP53, and ATM, among others. We found a pathogenic variant in ATM (c.3747-1G>C) in the index case patient and in her 24-year-old son. Given the described association of this gene with malignant neoplasms of the pancreas, the possible pancreatic neoplasia of the patient’s mother cannot be ignored, despite not having confirmation of pathological anatomy. Our unit has attempted to contact the patient’s brother, given his personal history of CM and ampulloma, in order to perform the genetic test. We have informed him of the importance for himself as well as for his offspring, having actively refused to undergo any type of genetic test. We also remain in contact with the patient to inform her if any of her 2nd-degree relatives have any neoplasia.

To date, no association of familial melanoma with the pathogenic variant ATM (c.3747-1G>C) described in this case has been published. In the bibliography found in PubMed redirected from ClinVar and OMIM, this variant has been described in the work of J. Mucaki et al. [24], and it only appears in supplementary Table 7 when it was described for the first time, without relation to any specific pathology and with a phenotypic prediction that consists of exon skipping and alternative splice forms. In this work, the authors conclude that the SVN found by NGS has the potential to produce deleterious changes [24]. In our family, members with CM are carriers of this variant; however, it cannot be excluded that the presence of CM is caused by chance, environmental interaction, another uncontrolled external factor, or the interaction of other genetic alterations other than the ATM variant described in this study.

We describe for the first time the possible association between ATM (c.3747-1G>C) and familial melanoma, and we also provide clinical evidence on the pathogenic nature of this particular variant. However, we cannot exclude that CM in both members and at an early age is the result of chance, environmental interaction, another uncontrolled external factor, or the interaction of other genetic alterations other than the ATM variant described in this study.

Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. Ethics board approval is not required for this case report in accordance with local guidelines.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Article processing charges (APC) are funded by IBIMA. The authors received no financial support for the research or authorship.

L.-S. G. reviewed the bibliography and checked ClinVar variants with their significance. L.-S. G., DR. T., and IC. M. wrote the main manuscript. M.-L. C. met the patients, made medical appointment, and got clinical information and informed consent from the patients. IC. M. and M.-L. C. made Figure 1. PP. J. and PP. JM. wrote case report methodology and reviewed genetics topics. All authors reviewed the manuscript.

Personal data are not available due to ethical and legal reasons. Further enquiries can be directed to the corresponding author.

1.
Ribeiro
J
,
Evangelista dos Santos
AC
,
de Moraes Lino da Silva
F
,
Machado
JR
,
de Melo
AC
.
“Molecular landscape of hereditary melanoma,” Critical reviews in oncology/hematology, vol. 164
.
Elsevier Ireland Ltd
. .
2.
Michielin
O
,
Van Akkooi
ACJ
,
Ascierto
PA
,
Dummer
R
,
Keilholz
U
,
Committee
G
.
Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
.
Cancer-related cognitive impairment
.
2019
;
30
:
1884
901
. .
3.
Hollestein
LM
,
van den akker
SAW
,
Nijsten
T
,
Karim-kos
HE
,
Coebergh
JW
,
de vries
E
.
Trends of cutaneous melanoma in The Netherlands: increasing incidence rates among all Breslow thickness categories and rising mortality rates since 1989
.
Ann Oncol
.
2012
;
23
(
2
):
524
30
. .
4.
Pastorino
L
,
Andreotti
V
,
Dalmasso
B
,
Vanni
I
,
Ciccarese
G
,
Mandalà
M
, et al
.
Insights into genetic susceptibility to melanoma by gene panel testing: potential pathogenic variants in acd, atm, bap1, and pot1
.
Cancers
.
2020
;
12
(
4
):
1007
. .
5.
Leachman
SA
,
Lucero
OM
,
Sampson
JE
,
Cassidy
P
,
Bruno
W
,
Queirolo
P
, et al
.
Identification, genetic testing, and management of hereditary melanoma
.
Cancer Metastasis Rev
.
2017
;
36
(
1
):
77
90
. .
6.
JH
Barrett
,
Iles
,
MM
,
Harland
,
M
,
Taylor
,
JC
,
Aitken
,
JF
,
Andresen
,
PA
, et al
.
“Genome-wide association study identifies three new melanoma susceptibility loci”
.
Nat Genet
.
2011
;
43
(
11
):
1108
13
. .
7.
Fang
S
,
Lu
J
,
Zhou
X
,
Wang
Y
,
Ross
MI
,
Gershenwald
JE
, et al
.
Functional annotation of melanoma risk loci identifies novel susceptibility genes
.
Carcinogenesis
.
2020
;
41
(
4
):
452
7
. .
8.
Goldstein
AM
,
Xiao
Y
,
Sampson
J
,
Zhu
B
,
Rotunno
M
,
Bennett
H
, et al
.
Rare germline variants in known melanoma susceptibility genes in familial melanoma
.
Hum Mol Genet
.
2017
;
26
(
24
):
4886
95
. .
9.
MT
Landi
,
Bishop
,
DT
,
MacGregor
,
S
,
Machiela
,
MJ
,
Stratigos
,
AJ
,
Ghiorzo
,
P
, et al
.
Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility”
.
Nat Genet
.
2020
;
52
(
5
):
494
504
. .
10.
Badenas
C
,
Aguilera
P
,
Puig-Butillé
JA
,
Carrera
C
,
Malvehy
J
,
Puig
S
.
Genetic counseling in melanoma
.
Dermatol Ther
.
2012
;
25
(
5
):
397
402
. .
11.
Potrony
M
,
Badenas
C
,
Aguilera
P
,
Puig-Butille
JA
,
Carrera
C
,
Malvehy
J
, et al
.
Update in genetic susceptibility in melanoma
.
Ann Transl Med
.
2015
;
3
(
15
):
210
. .
12.
Leachman
SA
,
Carucci
J
,
Kohlmann
W
,
Banks
KC
,
Asgari
MM
,
Bergman
W
, et al
.
Selection criteria for genetic assessment of patients with familial melanoma
.
J Am Acad Dermatol
.
2009
;
61
(
4
):
677.e1
677.14
. .
13.
Kastan
MB
,
Lim
D
.
The many substrates and functions of ATM
.
Nat Rev Mol Cell Biol
.
2000
;
1
(
3
):
179
86
. .
14.
Bonilla Sepúlveda
OA
.
Cáncer de mama y mutación del gen ataxia telangiectasia: reporte de caso
.
Horizmed
.
2023
;
23
(
1
):
e2036
. .
15.
Hart
SN
,
Polley
EC
,
Yussuf
A
,
Yadav
S
,
Goldgar
DE
,
Hu
C
, et al
.
Mutation prevalence tables for hereditary cancer derived from multigene panel testing
.
Hum Mutat
.
2020
;
41
(
8
):
e1
e6
. .
16.
Landi
MT
,
Bishop
DT
,
MacGregor
S
,
Machiela
MJ
,
Stratigos
AJ
,
Ghiorzo
P
, et al
.
Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility
.
Nat Genet
.
2020
;
52
(
5
):
494
504
. .
17.
Choi
M
,
Kipps
T
,
Kurzrock
R
.
ATM mutations in cancer: therapeutic implications
.
Mol Cancer Ther
.
2016
;
15
:
1781
91
. .
18.
Dalmasso
B
,
Pastorino
L
,
Nathan
V
,
Shah
NN
,
Palmer
JM
,
Howlie
M
, et al
.
Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia
.
Genet Med
.
2021
;
23
(
11
):
2087
95
. .
19.
Hall
MJ
,
Bernhisel
R
,
Hughes
E
,
Larson
K
,
Rosenthal
ET
,
Singh
NA
, et al
.
Germline pathogenic variants in the Ataxia Telangiectasia Mutated (ATM) gene are associated with high and moderate risks for multiple cancers
.
Cancer Prev Res
.
2021
;
14
(
4
):
433
40
. .
20.
“VCV000181950.13 - ClinVar - NCBI” [Online]
. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/181950/#id_first. (accessed September 26, 2023).
21.
Verhagen
MMM
,
Last
JI
,
Hogervorst
FBL
,
Smeets
DFCM
,
Roeleveld
N
,
Verheijen
F
, et al
.
Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype–phenotype study
.
Hum Mutat
.
2012
;
33
(
3
):
561
71
. .
23.
Feliubadaló
L
,
Moles-Fernández
A
,
Santamariña-Pena
M
,
Sánchez
AT
,
López-Novo
A
,
Porras
LM
, et al
.
A collaborative effort to define classification criteria for ATM variants in hereditary cancer patients
.
Clin Chem
.
2021
;
67
(
3
):
518
33
. .
24.
Mucaki
EJ
,
Caminsky
NG
,
Perri
AM
,
Lu
R
,
Laederach
A
,
Halvorsen
M
, et al
.
A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer
.
BMC Med Genomics
.
2016
;
9
(
1
):
19
. .