NOTCH1 encodes a member of the NOTCH family of proteins, which is a group of transmembrane receptors involved in the Notch signaling pathway. Notch signaling regulates cell fate decisions during development, and plays a crucial role in T cell development. Activating mutations of NOTCH1 including missense mutations and inframe inserstions/deletions in the heterodimerization(HD) domains either alone or together with missense, nonsense or frameshift (in/del) mutations in the C terminal PEST domain have been described in approximately 50% of cases of T-ALL. The HD domain or PEST domain mutations may occur together in cis (on the same allele) in ALL. NOTCH1 mutations are very rare in AML. However, NOTCH1 mutations are present in about 27% patients with T-myeloid mixed-phenotypeacute leukemia. The potential utility of therapeutic targeting of activating NOTCH1 mutations in these diseases remains to be elucidated.

NOTCH1 mutations have also recently been reported in approximately 10% of chronic lymphocytic leukemia and are typically PEST domain mutations in that disease. In CLL, NOTCH1 mutations and tend to be exlusive of SF3B1 mutations and possibly TP53 mutations, although some studies demonstrate that NOTCH1 mutations are associated with mutations of TP53. In CLL, the presence of NOTCH1 mutations has been associated with trisomy 12 and aggressive biologic features(CD38+, ZAP70+, unmutated IgH variable region) and adverse prognosis in some settings. The potential utility of therapeutic targeting of activating NOTCH1 mutations in these diseases remains to be elucidated.

This gene is a known cancer gene.

This gene is a known cancer gene.

NOTCH1 is a transmembrane receptor, which plays a role in cell fate determination, growth, and survival. Somatic activating mutations are common in T-cell lymphoblastic leukemia/lymphoma. Somatic alterations in NOTCH1 are very rare in colorectal adenocarcinoma and are identified in less than 1% of cases. NOTCH1 L2457V does not lie within any known functional domains of the NOTCH1 protein. L2457V has been identified in sequencing studies, but has not been biochemically characterized and therefore, its effect on protein function is unknown. The L2457V variant has been reported as a benign/likely benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/380420/). These results should be interpreted in the clinicopathologic context.

NOTCH1 is a transmembrane receptor, which plays a role in cell fate determination, growth, and survival. Somatic activating mutations are common in T-cell lymphoblastic leukemia/lymphoma. Somatic alterations in NOTCH1 are very rare in breast invasive ductal carcinoma and are identified in less than 1% of cases. NOTCH1 L2457V does not lie within any known functional domains of the NOTCH1 protein. L2457V has been identified in sequencing studies, but has not been biochemically characterized and therefore, its effect on protein function is unknown. The L2457V variant has been reported as a benign/likely benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/380420/). These results should be interpreted in the clinicopathologic context.

NOTCH1 is a transmembrane receptor that plays a role in various cellular processes including cell fate determination, growth, and survival. NOTCH1 may be somatically mutated in a variety of cancers, and these mutations can be either gain- or loss-of-function mutations depending on the tumor type. Translocations and activating somatic mutations in NOTCH1 have been identified in T-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. On the other hand, NOTCH1 loss-of-function somatic mutations are more common in solid tumors, namely squamous cell carcinomas, and occur as missense, frameshift or nonsense mutations. Somatic NOTCH1 mutations are rare in lung adenocarcinoma and are found in about 4% of cases. The NOTCH1 L2457V variant identified in this case has been reported as a benign germline finding in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/380420/). These results should be interpreted in the clinical context.

NOTCH1 is a transmembrane receptor, which plays a role in cell fate determination, growth, and survival. Notch signaling has been demonstrated to play a role in lung development and lung carcinogenesis. Notch activity is counteracted by NUMB. Gain-of-function mutations of NOTCH1 have been identified in approximately 10% of patients with non-small cell lung carcinoma (NSCLC). In addition, loss-of-function mutations in NUMB that allow for increased NOTCH1 activity have been observed in approximately 30% of NSCLC patients. Studies have observed that increased NOTCH1 expression is associated with a poor prognosis in patients with lung adenocarcinoma. The NOTCH1 intronic deletion variant (NM_017617:g.139397792_139397795del) is located nine base pairs downstream of exon 27. While the variant is located in close proximity to an exon-intron junction, a potential effect on gene splicing is unknown. These results should be interpreted in the clinical context.

NOTCH1 is a transmembrane receptor, which plays a role in cell fate determination, growth, and survival. Somatic alterations in NOTCH1 are very rare in thyroid carcinomas and are identified in less than 1% of cases. NOTCH1 L2457V does not lie within any known functional domains of the NOTCH1 protein. L2457V has been identified in sequencing studies, but has not been biochemically characterized and therefore, its effect on protein function is unknown. The L2457V variant has been reported as a benign/likely benign germline variant in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/380420/). These results should be interpreted in the clinicopathologic context.