Submissions for variant NM_000059.4(BRCA2):c.8206dup (p.Leu2736fs)

dbSNP: rs397507396

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241496	SCV000301252	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241496	SCV000327837	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018936	SCV005030559	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-19	criteria provided, single submitter	clinical testing	The c.8206dupC pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a duplication of C at nucleotide position 8206, causing a translational frameshift with a predicted alternate stop codon (p.L2736Pfs*28). This mutation has been reported in both breast and prostate cancer cohorts (Patel VL et al. Cancer Res, 2020 Feb;80:624-638; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Hodgson D et al. Ann Oncol, 2021 Dec;32:1582-1589). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355333	SCV001550196	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu2736Profs*28 variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs397507968) as "With Pathogenic allele", ClinVar (classified as pathogenic by ENIGMA and CIMBA), and in LOVD 3.0 (7x as pathogenic). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.8206dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2736 and leads to a premature stop codon at position 63. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in breast or 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.