Accurate variant classification is vital to ensuring appropriate medical management.

“There is a growing move to consult public databases following receipt of a genetic test result from a clinical laboratory; however, we show that up to 26.7% of variants in BRCA1 and BRCA2 have discordant classifications between ClinVar and a reference laboratory. The findings presented in this paper serve as a note of caution regarding the utility of database consultation.”

Gradishar W, et al. Clinical variant classification: A comparison of public databases and a commercial testing laboratory. Published ahead of print on April 13, 2017 as 10.1634/theoncologist.2016-0431.

View Article

Conflicting variant interpretations between commercial labs reported to PROMPT.

“We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments–approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. […] Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions.”

Balmaña J, et al. Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. J Clin Oncol 2016, 34: 4071-8. doi: 10.1200/JCO.2016.68.4316.

View Article

29% rate of discordance observed in variant interpretation.

“Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider.”

Amendola LM, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet 2016; 98(6):1067-76.

View Article

Substantial disparity of variant classifications among databases.

“Our results show substantial disparity of variant classifications among and within publicly accessible variant databases. Although locus-specific variant databases (LSDBs) have been well established for research applications, our results suggest that several challenges inhibit their wider use in clinical practice. Healthcare providers should exercise caution when using these research tools for clinical purposes.”

Vail PJ, et al. Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases. J Community Genet 2015 Oct; 6(4):351-9.

View Article

Clinical classification of hereditary sequence variants in disease-related genes directly affects clinical management of patients and their relatives.

“Carriers of mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 causing Lynch syndrome have a substantially increased risk of colorectal and endometrial cancers, along with increased risk of ovarian, gastric, small bowel, urothelial, brain, hepatobiliary, pancreatic, bladder, kidney, prostate and breast cancers. However, intensive management reduces mortality. […] InSiGHT has merged multiple gene mutation and variant repositories to create the InSiGHT Colon Cancer Gene Variant Database for MMR and other colon cancer susceptibility genes, hosted by the Leiden Open Variation Database (LOVD).”

Thompson BA, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature Genetics 2014; 46:107–115.

View Article