Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance

Abstract

It is important to identify a germline mutation in a patient with an inherited cancer syndrome to allow mutation carriers to be included in cancer surveillance programs, which have been proven to save lives. Many of the mutations identified result in premature termination of translation, and thus in loss‐of‐function of the encoded mutated protein. However, the significance of a large proportion of the sequence changes reported is unknown. Some of these variants will be associated with a high risk of cancer and have direct clinical consequence. Many criteria can be used to classify variants with unknown significance; most criteria are based on the characteristics of the amino acid change, on segregation data and appearance of the variant, on the presence of the variant in controls, or on functional assays. In inherited cancers, tumor characteristics can also be used to classify variants. It is worthwhile to examine the clinical, morphological and molecular features of a patient, and his or her family, when assessing whether the role of a variant is likely to be neutral or pathogenic. Here we describe the advantages and disadvantages of using the tumor characteristics of patients carrying germline variants of uncertain significance (VUS) in BRCA1, BRCA2, or in one of the mismatch repair (MMR) genes, MLH1, MSH2, or MSH6, to infer pathogenicity. Hum Mutat 29(11), 1292–1303, 2008. 2008 Wiley‐Liss, Inc.

Integrated analysis of unclassified variants in mismatch repair genes

“…The probabilities calculated were then classified in five classes, following the guidelines of the Special Issue of Human Mutation. [3][4][5][6][7][8][9][10][11][12] An increasing number of groups are trying to classify UVs using these recommendations, but most of them focus on the BRCA1 and BRCA2 genes, for which a multifactorial likelihood classification has already been developed and refined. Instead, for MMR genes, there are not well-established models or well-characterized features 42 so that, at the time of writing, a very few groups have attempted to classify MMR UVs with the Bayesian likelihood method.…”

EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients

“…Unfortunately, one half of the variations observed in the BRCA1/2 genes are UVs (Hofstra, et al, 2008), making biological and clinical interpretation a challenging task and consequently leading to clinically difficult situations. To facilitate subsequent genetic counseling, all identified UVs were submitted to in silico analysis using Alamut (Interactive Biosoftware), a decision-support system for mutation interpretation that integrates a splice prediction module.…”

Mammary Tumor Development in Dogs Is Associated with BRCA1 and BRCA2

“…A majority of the BRCA1/2 mutations reported cause protein truncation through indels, nonsense mutations, splice variants or rearrangements (18)(19)(20)(21). A large number of sequence variants with unknown effect on the phenotype have also been detected in BRCA1/2, and several studies have tried to determine their clinical significance (22,23).…”