Investigation of a germline variant of uncertain significance (MRE11:c.1138C > T) identified by exome sequencing in a cancer-affected individual and co-segregation analysis in affected and unaffected family members.

BACKGROUND: Cancer remains a significant global health concern, with familial cases often involving complex interactions between genetic predispositions and environmental factors. Variants of Uncertain Significance (VUS) pose challenges in genetic counseling and risk assessment, particularly in genes like MRE11, which plays a crucial role in DNA double-strand break repair and genomic stability.

METHODS AND RESULTS: This study aimed to investigate the effect of the MRE11 c.1138 C > T (p.Arg380Cys) variant in a family affected by familial cancer, focusing on its potential contribution to inherited cancer risk and the challenges it poses for genetic counseling in families with clustering of malignancies. Whole-exome sequencing was used to identify the variant, which was validated by Sanger sequencing. In silico protein modeling and bioinformatics analyses, including pathogenicity prediction tools like REVEL, SIFT, PolyPhen-2, and MutationTaster, were employed to assess the variant's functional effects. The MRE11 c.1138 C > T (p.Arg380Cys) variant was identified in a family with a history of breast, ovarian, and colorectal cancers.

CONCLUSIONS: Bioinformatics analyses suggested that this variant may destabilize the MRE11 nuclease domain, potentially impairing its function in DNA repair. Pathogenicity prediction tools consistently classified the variant as deleterious, although some family members with cancer did not carry the variant, indicating a complex interplay between genetic and environmental factors. The MRE11 p.Arg380Cys variant poses challenges in clinical interpretation due to its incomplete segregation within families. This pattern may reflect reduced penetrance, epistatic interactions with other genes (within MRN complex or others), or environmental influences.