Submissions for variant NM_000059.4(BRCA2):c.1054dup (p.Tyr352fs)

dbSNP: rs80359261

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031306	SCV000300383	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	RCV000130964	SCV000185879	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	clinical testing	The c.1054dupT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a duplication of T at nucleotide position 1054, causing a translational frameshift with a predicted alternate stop codon (p.Y352Lfs*6). This mutation has been reported multiple individuals with breast cancer (Rashidi A et al. Med. Oncol. 2015 Jan;32:371; Maxwell KN et al. Nat. Commun. 2017 08;8(1):319), as well as large cohorts of individuals who underwent BRCA1/2 testing (Dos Santos Vidal R et al. J Mol Diagn, 2016 05;18:362-369; 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768618	SCV000324884	pathogenic	Breast and/or ovarian cancer	2023-06-09	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031306	SCV000326488	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000365830	SCV000329132	pathogenic	not provided	2023-07-30	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; Not observed in large population cohorts (gnomAD); Observed in individuals with a personal and/or family history including breast, ovarian, and other cancers in published literature (Sinclair et al., 2002; Rashidi et al., 2015; Dos Santos Vidal et al., 2016; Maxwell et al., 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1282dupT; This variant is associated with the following publications: (PMID: 12097257, 26941049, 25428384, 28831036, 28152038, 30787465, 29446198, 20104584, 32885271, 35944511)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000257966	SCV000549801	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr352Leufs*6) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 25428384, 26941049, 28831036). This variant is also known as 1282insT. ClinVar contains an entry for this variant (Variation ID: 37725). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Molecular Medicine, Queen's University	RCV000257966	SCV000588076	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000031306	SCV000677668	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-12-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130964	SCV000903408	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000365830	SCV001716143	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	PVS1, PM2, PP4, PP5
Baylor Genetics	RCV003473154	SCV004210439	pathogenic	Familial cancer of breast	2022-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000257966	SCV004241760	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1054dupT (p.Tyr352LeufsX6) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 247576 control chromosomes (gnomAD). c.1054dupT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 29446198). Ten submitters (including ENIGMA expert panel) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031306	SCV000053911	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2008-11-20	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031306	SCV000145811	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000257966	SCV000587579	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356465	SCV001551642	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Tyr352Leufs*6 variant was identified in 6 of 61698 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer (Dos Santos Vidal 2016, Maxwell 2017, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359261) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seven other submitters; as likely pathogenic by Counsyl), and LOVD 3.0 (2x as pathogenic). The variant was not identified in the UMD-LSDB database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.1054dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 352 and leads to a premature stop codon at position 357. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer (HBOC) and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.