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While carriers of biallelic germline pathogenic variants (gPV) develop rare chromosomal instability syndromes, the cancer risk in heterozygotes remains controversial. We performed a systematic review and meta\u2010analysis of 53 studies in patients with different cancer diagnoses to better understand the cancer risk. We found an increased risk (odds ratio, 95% confidence interval) for gPV carriers in <jats:italic>NBN<\/jats:italic> for melanoma (7.14; 3.30\u201315.43), pancreatic cancer (4.03; 2.14\u20137.58), hematological tumors (3.42; 1.14\u201310.22), and prostate cancer (2.44, 1.84\u20133.24), but a low risk for breast cancer (1.29; 1.00\u20131.66) and an insignificant risk for ovarian cancer (1.53; 0.76\u20133.09). We found no increased breast cancer risk in carriers of gPV in <jats:italic>RAD50<\/jats:italic> (0.93; 0.74\u20131.16; except of c.687del carriers) and <jats:italic>MRE11<\/jats:italic> (0.87; 0.66\u20131.13). The secondary burden analysis compared the frequencies of gPV in MRN genes in patients from 150 studies with those in the gnomAD database. In <jats:italic>NBN<\/jats:italic> gPV carriers, this analysis additionally showed a high risk for brain tumors (5.06; 2.39\u20139.52), a low risk for colorectal (1.64; 1.26\u20132.10) and hepatobiliary (2.16; 1.02\u20134.06) cancers, and no risk for endometrial, and gastric cancer. The secondary burden analysis showed also a moderate risk for ovarian cancer (3.00; 1.27\u20136.08) in <jats:italic>MRE11<\/jats:italic> gPV carriers, and no risk for ovarian and hepatobiliary cancers in <jats:italic>RAD50<\/jats:italic> gPV carriers. These findings provide a robust clinical evidence of cancer risks to guide personalized clinical management in heterozygous carriers of gPV in the <jats:italic>MRE11<\/jats:italic>, <jats:italic>RAD50<\/jats:italic>, and <jats:italic>NBN<\/jats:italic> genes.<\/jats:p>","DOI":"10.1002\/ijc.35066","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T09:10:19Z","timestamp":1719393019000},"page":"1604-1615","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Germline pathogenic variants in the <i>MRE11<\/i>, <i>RAD50<\/i>, and <i>NBN<\/i> (<scp>MRN<\/scp>) genes in cancer predisposition: A systematic review and meta\u2010analysis"],"prefix":"10.1002","volume":"155","author":[{"given":"Barbora","family":"Stastna","sequence":"first","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine Charles University and General University 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