Prevalence of FANCM germline variants in BRCA1/2 negative breast and/or ovarian cancer patients from Pakistan

Fam Cancer. 2023 Jan;22(1):31-41. doi: 10.1007/s10689-022-00304-1. Epub 2022 Jul 8.


The Fanconi anemia complementation group M (FANCM) gene is a potential candidate for breast/ovarian cancer susceptibility in European populations. Here, we examined the contribution of FANCM germline variants to hereditary breast and/or ovarian cancer in Pakistan. Comprehensive FANCM variant screening was performed in 201 BRCA1 and BRCA2 (BRCA1/2) negative Pakistani patients with and without triple-negative breast cancer (TNBC) and/or ovarian cancer, using denaturing high-performance liquid chromatography analysis (DHPLC) followed by DNA sequencing. Novel variants were tested for their potential effect on protein function using in silico tools. Reverse transcription (RT)-PCR analysis of RNA extracted from one deletion/insertion (delins) variant (p.K1780delinsNGIT) carrier and three non-carriers was performed to evaluate the impact of this variant on splicing. Furthermore, potentially functional variants were evaluated in 200 healthy female controls. A missense variant (p.V1857M) was identified in a 50-year-old TNBC patient with a family history of breast cancer. It was also identified in the index patient´s daughter, who was diagnosed with osteosarcoma at 15 years of age. Further, one delins variant (p.K1780delinsNGIT) was identified in a 45-year-old non-TNBC patient, but not detected in her brother, who was diagnosed with Hodgkin's lymphoma at 38 years of age. Based on in silico and RNA analyses, p.V1857M and p.K1780delinsNGIT were predicted as variants of uncertain significance (VUS), respectively. Both variants were absent in 200 healthy controls. Our findings suggest a marginal contribution of FANCM variants to hereditary breast/ovarian cancer in Pakistan, which need to be confirmed in larger studies.

Keywords: FANCM; Germline alterations; Pakistan; TNBC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Breast Neoplasms* / epidemiology
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / pathology
  • DNA Helicases / genetics
  • Female
  • Genetic Predisposition to Disease
  • Germ Cells / pathology
  • Germ-Line Mutation
  • Humans
  • Male
  • Middle Aged
  • Ovarian Neoplasms* / epidemiology
  • Ovarian Neoplasms* / genetics
  • Pakistan / epidemiology
  • Prevalence
  • RNA
  • Triple Negative Breast Neoplasms* / epidemiology
  • Triple Negative Breast Neoplasms* / genetics


  • BRCA1 Protein
  • BRCA2 Protein
  • RNA
  • BRCA1 protein, human
  • FANCM protein, human
  • DNA Helicases

Supplementary concepts

  • Breast Cancer, Familial