Sulkava Sonja, Hakonen Anna H, Christensen Rikke, Pöyhönen Minna, Nevanlinna Heli
Department of Clinical Genetics, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Public Health, Finnish Institute for Health and Welfare, Helsinki, Finland.
Cancer Rep (Hoboken). 2025 Aug;8(8):e70283. doi: 10.1002/cnr2.70283.
Biallelic FANCM variants are linked to a Fanconi anemia-like cancer predisposition syndrome, which includes early onset breast cancer, chemotherapy toxicity, and chromosome fragility. Additionally, heterozygous truncating variants have been linked to increased breast cancer risk. However, the published results have been inconsistent, and the risks and the functional effects associated with the variants also vary depending on the position in the gene, with N-terminal truncating variants having a stronger effect. Compared to other FANCM variants studied, milder patient phenotypes and only late onset breast cancer have been reported for the homozygous C-terminal c.5101C>T variant, which is enriched in Finland.
We report here a Finnish patient, homozygous for the FANCM c.5101C>T p.(Gln1701*) variant, who manifested with early onset triple-negative breast cancer, chemotherapy toxicity, and chromosome fragility. Homozygosity for c.5101C>T has previously been reported in two Finnish siblings with primary ovarian insufficiency and chromosome fragility.
These findings suggest that the C-terminal FANCM variant c. 5101C>T may also be linked to a phenotype similar to the phenotype associated with N-terminal truncating variants when inherited in a homozygous state.
双等位基因FANCM变异与范可尼贫血样癌症易感性综合征相关，该综合征包括早发性乳腺癌、化疗毒性和染色体脆性。此外，杂合性截短变异与乳腺癌风险增加有关。然而，已发表的结果并不一致，与这些变异相关的风险和功能效应也因基因中的位置而异，N端截短变异的效应更强。与其他研究的FANCM变异相比，在芬兰富集的纯合C端c.5101C>T变异仅报告了较轻的患者表型和晚发性乳腺癌。
我们在此报告一名芬兰患者，其FANCM c.5101C>T p.(Gln1701*)变异呈纯合状态，表现为早发性三阴性乳腺癌、化疗毒性和染色体脆性。此前在两名患有原发性卵巢功能不全和染色体脆性的芬兰同胞中报告过c.5101C>T纯合性。
这些发现表明，C端FANCM变异c.5101C>T在纯合状态下遗传时，也可能与一种类似于与N端截短变异相关的表型有关。
