Submissions for variant NM_000059.4(BRCA2):c.5723_5724del (p.Leu1908fs)

dbSNP: rs886040608

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000256924	SCV000324371	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	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	RCV000256924	SCV000327271	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000481195	SCV000568164	pathogenic	not provided	2015-11-06	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in BRCA2 is denoted c.5723_5724delTA at the cDNA level and p.Leu1908ArgfsX2(L1908RfsX2) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 5951_5952delTA. The normal sequence, with the bases that are deleted in braces, is TCTC[TA]GATA. The deletion causes a frameshift, which changes a Leucine to an Arginine at codon 1908, and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Ambry Genetics	RCV000562013	SCV000661423	pathogenic	Hereditary cancer-predisposing syndrome	2017-04-11	criteria provided, single submitter	clinical testing	The c.5723_5724delTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5723 to 5724, causing a translational frameshift with a predicted alternate stop codon (p.L1908Rfs*2). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000256924	SCV001368586	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-10-10	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387051	SCV001587545	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-22	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 266893). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20683152, 29339979, 29446198, 30078507, 30720863). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu1908Argfs*2) 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). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000481195	SCV001548888	uncertain significance	not provided		no assertion criteria provided	clinical testing