The MLH1 c.1852_1853delinsGC (p.K618A) Variant in Colorectal Cancer: Genetic Association Study in 18,723 Individuals

Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance'', being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome. This work was supported by COST Action BM1206. Groups 1, 4, 5, 6, 7, 8, 10 and 13 are active members of this consortium. Edinburgh: This work was supported by a Cancer Research UK Programme Grant (C348/A12076) and a Centre Grant from the CORE Charity. Epicolon: SCB is supported by a contract from the Fondo de Investigacion Sanitaria (CP 03-0070). JM and CEJ are supported by contracts from the CIBERehd. CIBERehd and CIBERER are funded by the Instituto de Salud Carlos III. This work was supported by grants from the Fondo de Investigacion Sanitaria/FEDER (11/00219, 11/00681), Instituto de Salud Carlos III (Accion Transversal de Cancer), Xunta de Galicia (07PXIB9101209PR), Ministerio de Ciencia e Innovacion (SAF2010-19273), Asociacion Espanola contra el Cancer (Fundacion Cientifica GCB13131592CAST y Junta de Barcelona), Fundacio Olga Torres (SCB and CRP) and FP7 CHIBCHA Consortium (SCB and ACar). Kiel: This work was supported by the German Ministry for Education and Research through the German National Genome Research Network (NGFNplus) Colon Cancer Network (CCN). Leiden: This work was supported by the Dutch Cancer Society with grant KWF-UL-2005-3247. Stockholm: The Swedish sample and data resource were funded by the Swedish Cancer Society, the Swedish Scientific Research Council and the Stockholm Cancer Foundation. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.