Submissions for variant NM_000059.4(BRCA2):c.5119dup (p.Thr1707fs)

dbSNP: rs886040567

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000257633	SCV000324301	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	RCV000257633	SCV000327136	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199902	SCV001370659	pathogenic	Hereditary breast ovarian cancer syndrome	2020-05-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5119dupA (p.Thr1707AsnfsX11) 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 was absent in 231046 control chromosomes (gnomAD). c.5119dupA has been reported in the literature in families affected with Hereditary Breast and Ovarian Cancer Syndrome (Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported Two submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001199902	SCV001381146	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1707Asnfs*11) 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 clinical features of BRCA2-related conditions (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 266850). For these reasons, this variant has been classified as Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310154	SCV001499732	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002347978	SCV002645569	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-13	criteria provided, single submitter	clinical testing	The c.5119dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 5119, causing a translational frameshift with a predicted alternate stop codon (p.T1707Nfs*11). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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.