Submissions for variant NM_000059.4(BRCA2):c.5286T>G (p.Tyr1762Ter)

gnomAD frequency: 0.00001  dbSNP: rs80358754

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023865	SCV001185798	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-08	criteria provided, single submitter	clinical testing	The p.Y1762* pathogenic mutation (also known as c.5286T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 5286. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This variant has been reported in individuals diagnosed with ovarian cancer (Huang KL et al. Cell. 2018 Apr;173:355-370.e14). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063211	SCV001228048	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1762*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with prostate, breast, and/or ovarian cancer (PMID: 18445692, 29446198, 30130155). ClinVar contains an entry for this variant (Variation ID: 825619). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001023865	SCV001360137	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian cancer (PMID: 24448499, 26689913, 29625052; DOI: 10.31550/1727-2378-2018-154-10-43-46), pancreatic cancer (PMID: 35309086), and prostate cancer (PMID: 18445692, 23035815). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355845	SCV001550849	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Tyr1762X variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC Database, ARUP Laboratories, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.5286T>G variant leads to a premature stop codon at position 1762 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.