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Fibroblast testing can inform medical management in individuals with mosaic variants detected on hereditary cancer panels

      Highlights

      • Mosaic variants confirmed on fibroblast testing correlate well with clinical histories that are consistent with the germline condition.
      • NF1 mosaic pathogenic variants are often present likely as a result of clonal hematopoiesis (CH).
      • Presence of a mosaic variant in an individual with ovarian cancer, particularly if the variant is in a gene not linked to ovarian cancer risk, seems to signal CH as opposed to constitutional mosaicism.

      Abstract

      Mosaic variants are regularly detected on hereditary cancer genetic tests. While some of these variants may be constitutional, the majority are likely limited to blood lineages. In the present study, we correlate clinical histories from individuals with mosaic findings identified on hereditary cancer testing and the outcomes of follow-up fibroblast (FB) testing. We observed 620 mosaic variants, including 339 pathogenic or likely pathogenic variants (PVs) occurring most often in TP53, CHEK2, ATM, and NF1. About half of individuals with NF1 mosaic PVs did not report any clinical features of NF1 and were older at testing (p<0.0001) compared to those with an NF1-related phenotype. Among 42 mosaic PVs evaluated by FB testing, 17 (40.5%) were confirmed in FB and were mostly identified in individuals with phenotypes consistent with the gene disease spectrum. Our data show that FB testing is helpful for identifying those with likely constitutional mosaicism benefitting from increased screening and follow-up vs. those with blood-limited variants potentially not requiring intense surveillance but warranting further hematologic work-up.

      Keywords

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