Rare Occurrence of Dual MPL Exon 10 Mutations in a Patient With Thrombocytosis

Abstracts PALB2 is considered a high-risk cancer gene that is also associated with autosomal recessive Fanconi anemia subtype N. Loss-of-function PALB2 variants are associated with an increased risk for breast, ovarian, and pancreatic cancers. Reported breast cancer risk for females with pathogenic PALB2 mutations ranges from 33-58%, dependent upon family history; the risks for male breast, ovarian, and pancreatic cancers are not well defined. We identified a heterozygous nonsense PALB2 variant (c.3849C>A, Tyr1183*) in a female (38 years) with invasive ductal breast cancer and a family history of breast and pancreatic cancer. Targeted familial testing of ten members revealed paternal inheritance of this variant with incomplete segregation of breast cancer. Five family members without a history of breast, ovarian, or pancreatic cancer (ages 38–78) carry the variant, one of whom has a history of papillary thyroid cancer and melanoma and has a daughter who died of breast cancer (51 years) with no PALB2 testing. Of the five negative family members, one was diagnosed with ductal carcinoma in situ (55 years), one was diagnosed with breast cancer (60 years), and three (47, 53, and 63 years) are currently unaffected. Six members with breast or pancreatic cancer were not tested. Although PALB2 is associated with a high penetrance of breast cancer in patients with a strong family history, this association was not observed in the family members studied. The ability to access key family members is critical to determine whether a variant segregates with disease and to appropriately manage carriers of disease-causing variants.

41 Rare Occurrence of Dual MPL Exon 10 Mutations in a Patient With Thrombocytosis Durga Prasad Dash a, Amir Behdad b, Claudia Tellez b a Blood Center of Wisconsin, Milwaukee, WI, USA; bNorthwestern Medicine, Chicago, IL, USA

A 58 year old patient was presented to the clinic for evaluation of gradually worsening thrombocytosis, concerning for a possible myeloproliferative disease. The patient’s morphological findings in the bone marrow and sustained thrombocytosis in the peripheral blood are consistent with myeloproliferative neoplasm with a differential diagnosis that included essential thrombocythemia and prefibrotic myelofibrosis. The previous molecular tests for JAK2 and CALR mutations were negative for this patient and then it was tested for MPL Exon 10 mutation analysis. Mutation analysis of MPL exon 10 was performed by PCR amplification and direct sequencing (Sanger method). Mutation analysis revealed a MPL p.W515L mutation (NM_005373.2). Somatic mutations of codon 515 in exon 10 of the “myeloproliferative leukemia virus oncogene” (MPL) are found in an estimated 3–4% of patients with essential thrombocythemia (ET) and 7% of patients with primary myelofibrosis (PMF), including approximately 8.5% and 13% of JAK2 V617Fnegative ET and PMF patients, respectively (Vannucchi AM, et al. Blood 2008; Beer PA, et al. Blood 2008). Interestingly, a second MPL mutation c.1502T>C, p.V501A (NM_005373.2) was detected in this specimen which is reported in COSMIC database (COSM86964). This mutation does co-occur with the mutation p.W515L in patients with myeloproliferative neoplasm (Pietra D et al., Haematologica. 2011), however the pathogenic significance of the mutation (p.V501A) is not clear (Larissa V. Furtado et al., The Journal of Molecular Diagnostics,

45 2013; Langabeer et al., European Journal of Haematology, 2015). In conclusion, the occurrence of dual MPL mutations (p.W515L and p.V501A) in thrombocytosis patient is rare and the clinical significance of the MPL mutation p.V501A is unknown.

42 MolecularMatch LAB Integrates Knowledgebases for Collaborative Clinical Interpretation of Variation in Cancer Ryan Duren a, Shane Neeley a, James W. Welsh a,b, Nick Tackes a, Xuan S Li a, Caleb F. Davis a a MolecularMatch, Inc., Houston, TX, USA; bDepartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Many sites for collaborative curation of variants exist (CiVIC, Cancer Genome Interpreter, OncoKB, PMKB, JAX-Clinical Knowledgebase, etc.) but more are needed around the curation of individual scenarios, especially when interactions between multiple variants influence treatment decisions. Here we present an interface (MM-LAB) allowing users across institutions to collaborate on the interpretation of genomic variation in deidentified cancer patients. Content shared include publications and rationale from previous clinical interpretations. To illustrate the utility of this resource, we uploaded 200 cases from TCGA’s study of AML. We plan to expand the resource to all publicly available cases with cancer. To our knowledge this is the only resource facilitating public comments (anonymous or otherwise) on therapeutic and clinical trials recommendations for individual cancer patients. Navigation is provided by sorting and a search bar that filters cases by gene, variant, case identifier, etc. Anyone may view the resource, and registered users may add novel scenarios via uploading or creating new cases. Underlying the treatment and clinical trial recommendations is the MolecularMatch search engine (MM-DATA), which is also available by API. Briefly, MM-DATA consists of >1500 SNOMED cancer types, all known cancer variants, drugs, clinical trials, and publications. Clinical trials can be queried by locations and medical groups. All data are curated weekly to balance reliability and freshness of content. We hope to add search across other knowledgebases via GA4GH protocols developed by VICC. MM-LAB brings the variant curation community together around individual scenarios to stimulate interaction, share knowledge, and advance consensus in precision medicine. Conflict of Interest: While MolecularMatch is a for-profit organization, we believe sharing is critical for the utility of genomics data and wish to do our part. The company earns profits from subscriptions to MM-DATA

43 Molecular Diagnosis of Lung Cancers Kalal Iravathy Goud a, Kavitha Matam a, Adi Mahalakshmi Madasu a, Ravi Vempati a, Sagarika Darepalli a, Madhuri Pullemula a a Apollo Hospitals, Jubilee Hills, Hyderabad, India

Lung cancer is the leading cause of cancer-related deaths in the in the world. Molecular tests have been routinely used to