Submissions for variant NM_000059.4(BRCA2):c.8340_8343del (p.Asn2781fs)

dbSNP: rs80359707

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077434	SCV000301265	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.
Ambry Genetics	RCV000162939	SCV000213426	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	The c.8340_8343delTAAC pathogenic mutation, located in coding exon 18 of the BRCA2 gene, results from a deletion of 4 nucleotides from nucleotide positions 8340 to 8343, causing a translational frameshift with a predicted alternate stop codon (p.N2781Vfs*39). This mutation (designated as 8568delTAAC) was identified in one individual of Filipino descent with early onset ovarian cancer (Risch HA et al. J. Natl. Cancer Inst. 2006 Dec; 98(23):1694-706). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077434	SCV000327875	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000077434	SCV000487967	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000480653	SCV000568493	pathogenic	not provided	2022-11-07	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with breast and/or ovarian cancer (Risch et al., 2006; Litton et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 8568_8571del; This variant is associated with the following publications: (PMID: 17148771, 21324516, 21913181)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480653	SCV000600795	pathogenic	not provided	2016-11-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496829	SCV000942527	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn2781Valfs*39) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is also known as 8568delTAAC or 8568del4. ClinVar contains an entry for this variant (Variation ID: 52556). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162939	SCV001340339	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 19 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496829	SCV001448339	pathogenic	Hereditary breast ovarian cancer syndrome	2020-11-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8340_8343delTAAC (p.Asn2781ValfsX39) 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 251416 control chromosomes (gnomAD). c.8340_8343delTAAC has been reported in the literature in individuals affected with breast cancer or ovarian cancer (Risch_2006, Litton_2012, 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. Eight ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077434	SCV000109232	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-10-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077434	SCV000147327	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496829	SCV000587949	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research