Feng, B.-J. | bioRxiv Science

bioRxiv2019

A novel ribosomal protein 20 variant in a family with unexplained colorectal cancer and polyposis

Colorectal cancer (CRC) has a large hereditary component, which is only partially explained by known genetic causes. Recently, variants in ribosomal protein S20 (RPS20, [OMIM: 603682]) were identified in a family with familial CRC type X and in a CRC cancer case-control screen. This study describes a novel splice donor variant in RPS20, NM_001023.3:c.177+1G>A. It segregates with CRC [OMIM: 114500] and polyposis [HP: 0200063] within the probands family. Reverse transcription-polymerase chain reaction (RT-PCR) confirms the variant results in two aberrantly-spliced transcripts that are absent in controls. The location of the novel RPS20 variant is near two previously-reported truncating RPS20 variants associated with CRC. DNA from colon adenocarcinoma showed no evidence of loss-of-heterozygosity, supporting a haploinsufficiency or dominant negative disease mechanism. These findings support designation of RPS20 as a CRC predisposition gene, and expand the phenotypic spectrum of RPS20 truncating variants to include polyposis.

genetics↗

bioRxiv2019

Evaluation of ACMG Rules for In silico Evidence Strength Using An Independent Computational Tool Absent of Circularities on ATM and CHEK2 Breast Cancer Cases and Controls

The American College of Medical Genetics and Genomics (ACMG) guidelines for sequence variant classification include two criteria, PP3 and BP4, for combining computational data with other evidence types contributing to sequence variant classification. PP3 and BP4 assert that computational modeling can provide \"Supporting\" evidence for or against pathogenicity within the ACMG framework. Here, leveraging a meta-analysis of ATM and CHEK2 breast cancer case-control mutation screening data, we evaluate the strength of evidence determined from the relatively simple computational tool Align-GVGD. Importantly, application of Align-GVGD to these ATM and CHEK2 data is free of logical circularities, hidden multiple testing, and use of other ACMG evidence types. For both genes, rare missense substitutions that are assigned the most severe Align-GVGD grade exceed a \"Moderate pathogenic\" evidence threshold when analyzed in a Bayesian framework; accordingly, we argue that the ACMG classification rules be updated for well-calibrated computational tools. Additionally, congruent with previous analyses of ATM and CHEK2 case-control mutation screening data, we find that both genes have a considerable burden of pathogenic missense substitutions, and that severe ATM rare missense have increased odds ratios compared to truncating and splice junction variants, indicative of a potential dominant-negative effect for those missense substitutions.

genetics↗