Submissions for variant NM_004656.4(BAP1):c.1777C>T (p.Gln593Ter)

dbSNP: rs1064795638

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483505	SCV000571628	pathogenic	not provided	2016-09-09	criteria provided, single submitter	clinical testing	This variant is denoted BAP1 c.1777C>T at the cDNA level and p.Gln593Ter (Q593X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. McDonnell et al (2016) identified BAP1 Gln593Ter in an individual with a personal history of melanoma, thyroid neoplasia, basal cell carcinoma, and lymphoma and a family history of Spitz nevi, melanoma, and other cancers. Tumors from the proband and her sons demonstrated loss of the BAP1 protein by immunohistochemistry, and this variant segregated with disease in the family. We consider this variant to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763519	SCV000894325	pathogenic	BAP1-related tumor predisposition syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001013141	SCV001173685	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-11	criteria provided, single submitter	clinical testing	The p.Q593* pathogenic mutation (also known as c.1777C>T), located in coding exon 14 of the BAP1 gene, results from a C to T substitution at nucleotide position 1777. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This mutation has been described multiple individuals with BAP1-related cancers (McDonnell KJ et al. Cancer Genet, 2016 Mar;209:75-81; Garfield EM et al. J Am Acad Dermatol, 2018 Sep;79:525-534; Guo R et al. J Thorac Oncol, 2020 04;15:655-660). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000763519	SCV001586477	pathogenic	BAP1-related tumor predisposition syndrome	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln593*) in the BAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BAP1 are known to be pathogenic (PMID: 21874000, 23684012). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with BAP1 tumor predisposition syndrome (PMID: 26774355). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 422219). For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Medicine, Nationwide Children's Hospital	RCV000763519	SCV001748998	pathogenic	BAP1-related tumor predisposition syndrome	2021-07-09	criteria provided, single submitter	research	The c.1777C>T variant is predicted to cause a nonsense change at residue 593 of the BAP1 protein. It is absent from large public databases including gnomAD, and has been recently reported as pathogenic by multiple clinical laboratories. This variant was observed in a mother and daughter who developed meningiomas with rhabdoid features. We interpret the variant as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483505	SCV004221320	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	The BAP1 c.1777C>T (p.Gln593*) variant causes the premature termination of BAP1 protein synthesis. This variant has been reported in the published literature in individuals with meningioma (PMID: 34628055 (2022)), melanoma (PMID: 31887429 (2020)). The variant also has been observed in an individual with multiple cancers such as papillary thyroid cancer, b-cell lymphoma, and basal cell carcinoma (PMID: 26774355 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.