Collaborator: Albert Einstein College of Medicine

• Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein

  Abstract Missense mutations in the gene, MAP3K1, are a common cause of 46,XY gonadal dysgenesis, accounting for 15–20% of cases [Ostrer, 2014, Disorders of sex development (DSDs): an update. J. Clin. Endocrinol. Metab., 99, 1503–1509]. Functional studies demonstrated that all of these mutations cause a protein gain-of-function that alters co-factor binding and increases phosphorylation of the downstream MAP…

• Scaling resolution of variant classification differences in ClinVar between 41 clinical laboratories through an outlier approach

  Abstract ClinVar provides open access to variant classifications shared from many clinical laboratories. Although most classifications are consistent across laboratories, classification differences exist. To facilitate resolution of classification differences on a large scale, clinical laboratories were encouraged to reassess outlier classifications of variants with medically significant differences (MSDs). Outliers were identified by first comparing ClinVar…

• Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants

  Abstract The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast…

• A collaborative view of genomic variant interpretation: Clinical genetic counselors, laboratories, and patients

  April 2, 2026

• Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion

  Abstract The 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria, including a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on specific considerations for the different types of loss of function variants, nor did it provide…

• Scaling the Resolution of Sequence Variant Classification Discrepancies in ClinVar

  The first phase of this project involved ClinVar submissions from 41 clinical laboratories, and found that 84.6% of classifications were concordant and only 2.7% (650 variants) of variants were medically significant differences (MSDs) with potential to impact medical management. Of the discrepant results that  have been reviewed, 62.3% have now been resolved through data sharing…

  April 2, 2026

• De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

  Abstract Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals…

• Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing

  Abstract Background Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor–negative, progesterone receptor–negative, human epidermal growth factor receptor–negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of…

• Multigene Hereditary Cancer Panels Reveal High-Risk Pancreatic Cancer Susceptibility Genes

  Abstract Purpose The relevance of inherited pathogenic mutations in cancer predisposition genes in pancreatic cancer is not well understood. We aimed to assess the characteristics of patients with pancreatic cancer referred for hereditary cancer genetic testing and to estimate the risk of pancreatic cancer associated with mutations in panel-based cancer predisposition genes in this high-risk…

• The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change