MCPH1 and DNA Damage Response Pathway Genes as Candidate Susceptibility Loci in Hereditary Breast Cancer

Background/Objectives: Standard hereditary breast cancer gene panels fail to identify causative variants in some patients meeting hereditary breast and ovarian cancer (HBOC) criteria. This exploratory, hypothesis-generating study characterised germline variants in MCPH1, functionally related DNA damage response genes, and selected low-evidence candidate genes in breast cancer patients with uninformative standard panel results. Methods: A total of 185 patients meeting NCCN/ACMG criteria, with normal 42-gene panel and BRCA1/2/PALB2 MLPA results, underwent second-tier targeted sequencing. Group 1 comprised MCPH1 and related genes (TP53BP1, MDC1, TOPBP1, UBE2N, RAD52); Group 2 consisted of Genomics England PanelApp candidates (ATRIP, ESR1, PPM1D, RAD54L, RRAS2, XRCC2). No ethnically matched control cohort was available. Variants were classified per ACMG 2015 guidelines and confirmed by Sanger sequencing. Results: Rare variants meeting reporting criteria were identified in 20/185 patients (10.8%): one likely pathogenic (LP) MCPH1 frameshift deletion (c.1869_1870del) in a luminal B invasive ductal carcinoma patient, nineteen variants of uncertain significance (VUS), and one unconfirmed copy number variant. ATRIP was the most frequently implicated Group 2 gene (4 patients), including a homozygous variant; RAD54L variants were identified in three patients, including the only male breast cancer case. Conclusions: These descriptive findings identify MCPH1, ATRIP, MDC1, TOPBP1, and RAD54L as candidates warranting evaluation in case–control studies with ancestry-matched cohorts, functional validation, and family segregation analysis before any consideration for panel inclusion.