Exploring the Melanoma and Pancreatic Cancer Phenotype of a Potential <i>CDKN2A</i> Founder Variant, I49T (c.146T>C; p.Ile49Thr), in Individuals of Predominantly Mexican Ancestry.

Abstract

Pathogenic/likely pathogenic variants (P/LPVs) in the <i>CDKN2A</i> gene cause an increased risk of melanoma (MEL) and pancreatic cancer (PANC). The <i>CDKN2A</i> variant I49T (c.146T>C), reported to be recurrent in Hispanics, has conflicting pathogenicity classifications at laboratories, affecting clinical care. Multiple genetics clinics collaborated to explore cancers associated with I49T. Institutional clinical databases were queried for the <i>CDKN2A</i> variants, I49T, known P/LPVs, and c.-2G>A (a benign variant [BV]), and history of PANC and MEL was abstracted. A combination of statistical tests was used to investigate cancer history associations. Data on 203 individuals, with qualifying <i>CDKN2A</i> variants detected on multigene testing between 2012 and 2023, were analyzed (I49T, n = 101; known <i>CDKN2A</i> P/LPVs, n = 57; BV, n = 45). Those with I49T were 91% less likely to have MEL than known <i>CDKN2A</i> P/LPVs (odd ratio [OR] = 0.089 [95% CI, 0.031 to 0.025]; <i>P</i> < .001) and were also less likely to have PANC (OR = 0.45 [95% CI, 0.14 to 1.41]; <i>P</i> = .17). However, mean age at PANC diagnosis for I49T was 56.0 years, significantly younger than known <i>CDKN2A</i> P/LPVs (μ = 71.0 years; <i>P</i> = .026). In the largest I49T study to date to our knowledge, MEL was significantly less frequent compared with known <i>CDKN2A</i> P/LPVs. Although a nonsignificant trend was observed for less PANC in I49T than known P/LPVs, individuals with I49T presented with PANC at a significantly younger age than those with known <i>CDKN2A</i> P/LPVs. The presence of I49T in Hispanics of mostly Mexican ancestry supports that it is a founder variant, relevant to understanding cancer risk in a large proportion of Hispanics in the United States.