Submissions for variant NM_000059.4(BRCA2):c.6129dup (p.Gly2044fs)

dbSNP: rs80359561

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)	RCV000113535	SCV000300986	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481411	SCV000296542	pathogenic	not provided	2016-04-09	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113535	SCV000327359	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000481411	SCV000568473	pathogenic	not provided	2016-05-16	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in BRCA2 is denoted c.6129dupA at the cDNA level and p.Gly2044ArgfsX5 (G2044RfsX5) at the protein level. The normal sequence, with the base that is duplicated in braces, is CAAAA[A]GGCT. The duplication causes a frameshift which changes a Glycine to an Arginine at codon 2044, and creates a premature stop codon at position 5 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. BRCA2 c.6129dupA, also known as BRCA2 6357dupA by alternate nomenclature, has been identified in an individual undergoing testing for Hereditary Breast and Ovarian Cancer (Frank 2002, Phelan 2002). We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382369	SCV001581117	pathogenic	Hereditary breast ovarian cancer syndrome	2017-07-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This sequence change creates a premature translational stop signal (p.Gly2044Argfs*5) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with breast and/or ovarian cancer (PMID: 12402332, 22430266). This variant is also known as 6357insA in the literature. ClinVar contains an entry for this variant (Variation ID: 52018).
Ambry Genetics	RCV002354238	SCV002661300	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-05	criteria provided, single submitter	clinical testing	The c.6129dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 6129, causing a translational frameshift with a predicted alternate stop codon (p.G2044Rfs*5). This alteration has been identified in multiple patients referred for evaluation due to personal and/or family history of breast and/or ovarian cancer and was identified in a large, worldwide study of BRCA1/2 mutation positive families (Finkelman BS et al. J. Clin. Oncol., 2012 Apr;30:1321-8; Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also designated as 6357insA in published literature. 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113535	SCV000146774	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2001-01-17	no assertion criteria provided	clinical testing