The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

摘要: Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG→GCG) leading to substitution lysine alanine in codon 618, has variously been interpreted as pathogenic mutation, variant unknown significance, and benign polymorphism. We evaluated the role K618A predisposition by genotyping 1512 control subjects assess its frequency general population. also reviewed literature concerning families with colorectal cancer. The measured allele was 0.40%, is remarkably close 0.44% summarized 2491 literature. over-represented suspected Lynch syndrome. In 1366 families, 0.88% (OR = 2.1, 95% CI 1.3 3.5; P 0.006). studies sporadic cancers type associated syndrome, 1742 cases (allele 0.83) 2.0, 1.2 3.2; 0.008). conclude that not fully penetrant syndrome although it without effect, appearing increase risk syndrome-associated tumors approximately twofold. Our systematic assessment approach may useful other genes.