eP045: Papillary renal cell carcinoma, glioma and colon polyps in a patient with novel POT1 variant


      POT1 tumor predisposition (POT1-TPD) is a rare autosomal dominant cancer susceptibility syndrome with fewer than 100 families reported in the literature. It is caused by heterozygous pathogenic variants in the POT1 (protector of telomeres 1) gene. Core cancers associated with POT1-TPD include cutaneous melanoma, chronic lymphocytic leukemia (CLL), glioma and cardiac angiosarcoma. Limited evidence suggests that other associated cancers may include colorectal, thyroid and breast angiosarcomas. Less than 100 families have been identified with POT1-TPD to date.
      POT1 is part of the telomere shelterin complex which facilitates telomere protection and access. The majority of variants identified in this gene are classified as of uncertain significance due to insufficient data based on ACMG classification criteria.

      Case presentation

      We present a 56 year old woman with history of chronic left back pain. CT imaging showed a heterogeneously enhancing left renal mass concerning for malignancy. The patient underwent a radical nephrectomy and was diagnosed with papillary renal cell carcinoma (RCC), type 2. She reported a strong, but limited family history of cancer including a brother with lymphoma, mother and maternal aunt with melanoma, father who developed lung cancer and had history of smoking and multiple maternal and paternal relatives with cancer diagnoses of unknown primary. A multi-gene cancer panel revealed a heterozygous likely pathogenic variant in POT1 (NM_015450.3(POT1):c.125-2A>G). She had a recent colonoscopy which was significant for 8 colon polyps (6 hyperplastic, 2 tubular adenomas) and underwent polypectomy. Follow up brain MRI was ordered based on POT1-associated cancer risks. This revealed a left orbitofrontal lesion with findings suggestive of primary glial neoplasm. The patient underwent craniotomy and was diagnosed with a grade 2 glioma with future plans to treat with radiation therapy and systemic chemotherapy. Due to the POT1-TDP-related cancer, family history of related cancer, and likely pathogenic variant, the patient was diagnosed with POT1-TDP.
      The patient has past medical history of headache and obesity. She has a 15 year history of tobacco use with smoking a half pack of cigarettes per day which was discontinued 10 years prior to her presenting for medical attention. She reports moderate alcohol consumption with 4 to 5 drinks per week.


      This is to our knowledge, the first reported case of papillary RCC in a person with POT1-TPD. POT1-TPD has a clear association with cutaneous melanoma, glioma and angiosarcoma. There are patients described with family history of renal cancer; however, those family members did not have genetic testing so it is unknown if they have the POT1 familial variant. Interestingly, POT1 is functionally expressed in human embryonic kidney, making it plausible that it increases risk for kidney cancer. While the patient has some risk factors for RCC, we cannot exclude the possibility that the RCC is associated with her diagnosis of POT1-TDP. Due to the rarity of POT1-TPD it is unclear if additional cancers outside of the core-described cancers are associated with this gene. Further studies are needed to define the POT1-TPD tumor spectrum and risks.
      The POT1 c.125-2A>G variant has not been reported in the literature and is not present in population databases. It is classified by the performing laboratory as likely pathogenic. This variant affects an acceptor splice site in intron 6 of the POT1 gene and is predicted to result in aberrant RNA splicing. Description of this variant in a patient with a core cancer diagnosis (and with family history of core cancer diagnoses) supports the classification as likely pathogenic and may assist in the interpretation of future sequencing results.