A Novel Germline Frameshift Variant in the Tumor Suppressor Gene OBSCN in a Melanoma Patient

TL;DR

A new germline mutation in the OBSCN tumor suppressor gene was found in a melanoma patient, suggesting it may contribute to melanoma risk.

Contribution

This is the first report of a germline frameshift variant in OBSCN associated with melanoma.

Findings

A novel heterozygous frameshift variant in OBSCN was identified in a melanoma patient.

The variant introduces a premature stop codon and is classified as likely pathogenic.

This finding expands the genetic landscape of melanoma predisposition.

Abstract

Malignant melanoma is a complex malignancy with genetic, environmental, and lifestyle factors in its etiology. While germline variants in melanoma predisposition genes have been described, many patients remain genetically unexplained after panel testing. We previously analyzed a Hungarian melanoma cohort (n = 17), identifying variants in predisposing or susceptibility genes in 58.82% of patients. For individuals negative on this melanoma-specific panel, we expanded testing to a 19-gene panel associated with multiple cancer types. Next-generation sequencing was performed, followed by Sanger sequencing for confirmation. Variants were classified according to ACMG guidelines. In a 58-year-old female patient with a history of primary cutaneous melanoma, we identified a novel heterozygous frameshift variant in the tumor suppressor gene OBSCN (c.21322_21323insCTGG, p.G7108AfsTer10; NM_001386125.1). This insertion introduces a premature stop codon in exon 89 within the immunoglobulin-like domain, predicting protein truncation. Classified as likely pathogenic (PVS1, PM2), the variant is absent from population databases. To date, somatic OBSCN mutations have been reported in melanoma. This first report of a germline OBSCN frameshift variant in melanoma expands the genetic landscape of melanoma predisposition and suggests that OBSCN may represent a candidate gene contributing to melanoma risk.

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