8-Oxoguanine, a common mutagenic DNA lesion, generates G:C > T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C > T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co‐segregation, family cancer history profile, co‐occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case‐control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene‐specific calibration of evidence types used for variant classification.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a cancer-predisposing condition caused by inactivating mutations in at least four genes (MSH2, MLH1, MSH6, and PMS2) belonging to the mismatch repair system. At present, availability of the microsatellite instability (MSI) test allows screening of a relevant fraction of patients with a constellation of features suggestive of HNPCC. By analogy with several other genetic disorders, it is clearly emerging that the term HNPCC encompasses a wide spectrum of different clinical presentations, including Muir-Torre syndrome, Turcot syndrome, and the neurofibromatosis-hematological malignancy association. Notwithstanding the remarkable genetic and allelic heterogeneity, a few consistent phenotype-genotype associations can be recognized. Mutations in the MSH2 gene entail higher risks of developing cancer, including extraintestinal ones, than MLH1 alterations. MSH2 also accounts for most cases of Muir-Torre syndrome, which is characterized by the presence of sebaceous skin tumors. The few known PMS2 mutations show a striking association with the presence of gliomas, which are the hallmark of the Turcot variant of HNPCC. Homozygotes for mismatch repair gene mutations present with stigmata of neurofibromatosis 1 and usually die in childhood due to a variety of leukemias and lymphomas. While such correlations are being defined, the underlying reasons have only partially been elucidated, and may include heterogeneous gene functions and properties; types of mutation, some of which may exert dominant negative effects; and genetic and environmental modifiers.