Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility

Abstract

PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.

The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

“…FA is a hereditary recessive bone marrow failure and cancer predisposition syndrome. To date, 21 genes have been associated with FA; all of them encode proteins involved in DNA interstrand crosslink repair . One of the FA‐genes, FANCM , has recently been excluded as a gene predisposing for FA but has been suggested as a predisposition gene for hereditary breast cancer .…”

“…Both associations are in line with our own data. The nonsense PV FANCM:c.5101C>T p.(Gln1701*) PV is relatively common in the Finnish population and has been associated with an increased risk for breast cancer . The nonsense PV FANCM:c.5791C>T, p.(Gly1906Alafs*12) also known as p.(Arg1931*), is possibly more frequent in Southwestern Europeans .…”

“…The nonsense PV FANCM:c.5101C>T p.(Gln1701*) PV is relatively common in the Finnish population and has been associated with an increased risk for breast cancer . The nonsense PV FANCM:c.5791C>T, p.(Gly1906Alafs*12) also known as p.(Arg1931*), is possibly more frequent in Southwestern Europeans . The latter variant induces skipping of exon 22, which leads to the formation of a truncated protein .…”

“…To date, 21 genes have been associated with FA; all of them encode proteins involved in DNA interstrand crosslink repair. [43][44][45] One of the FA-genes, FANCM, has recently been excluded as a gene predisposing for FA but has been suggested as a predisposition gene for hereditary breast cancer. 21,22,33,45 FANCM is one of the eight FA-genes that form the FA core complex, responsible for monoubiquitination of FANCI/D2, which is a crucial step for its recruitment to the site of DNA damage.…”

“…45 The nonsense PV FANCM: c.5791C>T, p.(Gly1906Alafs*12) also known as p.(Arg1931*), is possibly more frequent in Southwestern Europeans. 45 The latter variant induces skipping of exon 22, which leads to the formation of a truncated protein. 22 Both nonsense PVs were identified twice in our own cohort (Table 1).…”