paywalled: Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation - Wiley Online Library

Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation

Abstract

Mismatch repair (MMR) malfunction causes the accumulation of mismatches in the genome leading to genomic instability and cancer. The inactivation of an MMR gene (MSH2, MSH6, MLH1 or PMS2) with an inherited mutation causes Lynch syndrome (LS), a dominant susceptibility to cancer. MMR gene variants of uncertain significance (VUS) may be pathogenic mutations which cause LS, may result in moderately increased cancer risks, or may be harmless polymorphisms. Our study suggests that an inherited MMR VUS individually assessed as proficient may, however, in a pair with another MMR VUS found in the same colorectal cancer (CRC) patient have a concomitant contribution to the MMR deficiency. Here, eight pairs of MMR gene variants found in cancer patients were functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild type MSH2 protein, is presumed to increase the cancer risk considerably. Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C (p.Leu585Pro), were shown to be MMR deficient. The role of one of the most frequently reported MMR gene VUS, MSH2 c.380A>G (p.Asn127Ser), is especially interesting, since its concomitant defect with another variant could finally explain its recurrent occurrence in CRC patients.

Cancers | Free Full-Text | The Clinical Significance of Unknown Sequence Variants in BRCA Genes

LOVD - An Open Source DNA variation database system (eg. genetic testing/unknown clinicial variant/s)

LOVD stands for Leiden Open (source) Variation Database.
LOVD's purpose : To provide a flexible, freely available tool for Gene-centered collection and display of DNA variations.

Mutalyzer

LOVD features integration with the Mutalyzer sequence variant nomenclature checker, allowing for direct nomenclature checking of sequence variants during the submission process.

If you are looking for a specific gene database, please check the list of gene variant databases at the HGVS site, in our list of LSDBs, or in the list of registered LOVD installations.

Understanding Patient Perspectives on Communication About the Cost of Cancer Care: A Review of the Literature — JOP

Conclusion: To my knowledge, patient preferences surrounding discussion of cost of cancer care have gone largely unstudied and are thus unknown. If the goal is to provide high-quality care while controlling rising health care costs, more research is needed to better understand patient perspectives on communication surrounding the cost of oncologic care, particularly given the significant impact such discussions may have on cancer outcomes, cost, and overall patient satisfaction.

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA 1 by Structural and Functional Assays

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays.

Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS, Yeung T, Foo D, Hau DD, Hui B, Monteiro AN, Glover JN.

Authors' Affiliations: Department of Biochemistry, School of Systems Molecular Medicine, University of Alberta, Edmonton, Alberta, Canada; National Institute of Environmental Health Sciences, Durham, North Carolina; Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; and Molecular Biology Program, Institute of Biophysics Carlos Chagas Fo., Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Abstract

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer....... Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.

Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts

BACKGROUND:
Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2.

CONCLUSIONS:
These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.