Dataset Information

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

ABSTRACT: While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.

SUBMITTER: Brown KM

PROVIDER: S-EPMC8720902 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

Brown Kevin M KM Xu Mai M Sargen Michael M Jang Hyunbum H Zhang Mingzhen M Zhang Tongwu T Zhu Bin B Jones Kristie K Kim Jung J Mendoza Laura L Hayward Nicholas K NK Tucker Margaret A MA Goldstein Alisa M AM Yang Xiaohong Rose XR Stewart Douglas R DR Hicks Belynda B Consonni Dario D Pesatori Angela C AC Fargnoli Maria Concetta MC Peris Ketty K Stratigos Alex A Menin Chiara C Ghiorzo Paola P Puig Susana S Nagore Eduardo E Andresson Thorkell T Nussinov Ruth R Calista Donato D Landi Maria Teresa MT

Familial cancer 20210703 3

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individual ...[more]

PMID: 34215961

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Project description:BackgroundFamilial adenomatous polyposis (FAP) is caused by pathogenic germline variants in the APC gene. To date, multiple pathogenic variants in coding regions, splice sites, and deep intronic regions have been revealed. However, there are still pathogenic variants that remain unidentified.MethodsTwenty-nine primer pairs flanking exons 2-16 (i.e., coding exons 1-15) of APC and their exon-intron junctions were used for germline pathogenic variant screening in Southern Thai patients with familial adenomatous polyposis (FAP). Transcription analysis was performed to confirm the pathogenicity of a splice site deletion of intron 10. Family members were interviewed for clinical histories. Blood samples were collected from 18 family members for a segregation study. Subsequently, clinical data of affected members were collected from the hospital databases.ResultsWe found a distinct heterozygous 16-bp deletion at the splice donor site of intron 10 leading to a skipping of exon 10 which was confirmed by transcript analysis (APC: c 1312 + 4_1312 + 19del, r.934_1312del). Predictive testing for the pathogenic APC variant in 18 of the proband's family members (ten healthy and eight affected) from three generations showed the same heterozygous germline pathogenic variant in eight affected adult members (15-62 years old) and two children (7 and 10 years old). Seven of the ten carriers of the disease-causing variant had undergone colonoscopy, and colonic polyps were found in all cases, which confirmed the segregation of the inherited pathogenic variant. The phenotypic spectrum was found to vary within the family; and some affected family members exhibited extracolonic manifestations.ConclusionsTo our knowledge, the pathogenic APC variant, c.1312 + 4_1312 + 19del, r.934_1312del, has not previously been reported. This study is one of the few reports describing the phenotypic consequences of a pathogenic APC variant in a high number of affected family members.

Dataset Information

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

Publications

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

Similar Datasets

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