FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor. Issue 12 (29th October 2020)

• Record Type: Journal Article
• Authors: Cannon‐Albright, Lisa A.; Teerlink, Craig C.; Stevens, Jeffrey; Snow, Angela K.; Thompson, Bryony A.; Bell, Russell; Nguyen, Kim N.; Sargent, Nykole R.; Kohlmann, Wendy K.; Neklason, Deborah W.; Tavtigian, Sean V.
• Is Part Of: Molecular genetics & genomic medicine. Volume 8:Issue 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-10-29
• Subjects: colorectal cancer -- FANCM -- high‐risk pedigree -- UPDB; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1532
• Languages: English
• ISSNs: 2324-9269

Abstract

ABSTRACT: Purpose: While familial aggregation of colorectal cancer (CRC) is recognized, the majority of the germline predisposition factors remain unidentified, and many high‐risk CRC pedigrees remain unexplained by known risk variants. Fanconi Anemia genes have been recognized to be associated with cancer risk. Notably, FANCM (OMIM 609644) variants have been reported to confer risk for CRC and breast cancer. Methods: Exome sequencing of CRC‐affected cousins in a set of 47 independent extended high‐risk CRC pedigrees identified a candidate set of rare, shared variants. Variants were tested for association with risk in 744 Utah CRC cases and 1525 controls, and for segregation with CRC in affected relatives. Results: A FANCM stopgain variant was observed in two CRC‐affected cousin pairs, each from an independent Utah high‐risk pedigree, and yielded a nonsignificant, but elevated OR = 2.05 in a set of Utah cases and controls. Segregation of the variant to other related CRC‐affected cases was observed in the two extended pedigrees. Conclusion: A rare stopgain variant in FANCM (rs144567652) that is recognized as a breast cancer predisposition variant, and that has previously been proposed, but not confirmed, as a CRC predisposition variant, is validated here as a risk factor for familial CRC. Abstract : This manuscript reports a unique and efficient study design including high‐risk pedigrees to identify strong candidate predisposition variants for colorectal cancer. It validates a FANCM risk variant previously reported as associated with colorectal cancer, but not confirmed. These confirmatory findings include two segregating high‐risk pedigrees and provide information useful for clinical guidance for carriers with respect to cancer risk.