Submissions for variant NM_000059.4(BRCA2):c.6859_6863del (p.Arg2287fs)

dbSNP: rs398122568

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478767	SCV000566500	pathogenic	not provided	2015-05-04	criteria provided, single submitter	clinical testing	This deletion of 5 nucleotides in BRCA2 is denoted c.6859_6863delAGAAA at the cDNA level and p.Arg2287LeufsX4 (R2287LfsX4) at the protein level. The normal sequence, with the bases that are deleted in braces, is CAAA[AGAAA]CTTA. The deletion causes a frameshift, which changes an Arginine to a Leucine at codon 2287, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although This variant, also known as BRCA2 7087_7091delAGAAA using alternate nomenclature, has not, to our knowledge, been reported in the literature, the adjacent mutation BRCA2 c.6856delAAAAG, which also results in a frameshift at this residue (p.Arg2287LeufsX4), has been reported in at least one individual with early-onset prostate cancer (Edwards 2003, 2010). we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800123	SCV000939823	pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2287Leufs*4) 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 present in population databases (rs398122568, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 12474142, 20043088). This variant is also known as 7084delAAAAG and 6856delAAAAG. ClinVar contains an entry for this variant (Variation ID: 91461). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001025735	SCV001187981	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-06	criteria provided, single submitter	clinical testing	The c.6859_6863delAGAAA variant, located in coding exon 11 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6859 to 6863, causing a translational frameshift with a predicted alternate stop codon (p.R2287Lfs*4). This alteration was reported in a cohort of prostate cancer patients (Mitra AV et al. Oncol. Rep. 2010 Feb;23:299-305). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay; however, this variant occurs in an exon that is absent in biologically relevant transcripts (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80; Fackenthal JD et al. J. Med. Genet. 2016 08;53:548-58). Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000800123	SCV001362827	pathogenic	Hereditary breast ovarian cancer syndrome	2019-09-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6859_6863delAGAAA (p.Arg2287LeufsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 246146 control chromosomes. c.6859_6863delAGAAA has been reported in the literature as associated with poor survival in at-least one individual affected with Prostate Cancer (Edwards_2003, Mitra_2008, Edwards_2010, Castro_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000076978	SCV000108775	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2008-08-13	no assertion criteria provided	clinical testing