Submissions for variant NM_000059.4(BRCA2):c.6833_6837del (p.Ile2278fs)

dbSNP: rs80359626

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)	RCV000113656	SCV000301112	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	RCV000162934	SCV000213421	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	The c.6833_6837delTCTTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6833 to 6837, causing a translational frameshift with a predicted alternate stop codon (p.I2278Sfs*13). This alteration has been identified in a breast and an ovarian cancer cohort (Gayther SA et al. Nat. Genet. 1997 Jan;15(1):103-5; Cardoso FC et al. Hum. Genomics. 2018 08;12(1):39). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000113656	SCV000327530	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000478267	SCV000568478	pathogenic	not provided	2024-07-25	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 a personal or family history consistent with pathogenic variants in this gene (PMID: 22762150, 30103829, 32341426); 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 7061_7065del; This variant is associated with the following publications: (PMID: 8988179, 12036913, 29446198, 22762150, 31853058, 32341426, 31341520, 30103829, 34072659, 33471991)
Counsyl	RCV000113656	SCV000786272	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162934	SCV000911672	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 11 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 been reported in at least 4 individuals affected with breast and ovarian cancer (PMID: 12036913, 30103829, 32341426, 33471991; Leiden Open Variation Database DB-ID BRCA2_003427, 34072659) and has been identified in 5 families among the CIMBA participants (PMID: 29446198). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496350	SCV001578454	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52203). This variant is also known as c.7057del5. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8988179, 30103829). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile2278Serfs*13) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496350	SCV001737856	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6833_6837delTCTTA (p.Ile2278SerfsX13) 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 250196 control chromosomes. c.6833_6837delTCTTA 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003473390	SCV004212873	pathogenic	Familial cancer of breast	2021-12-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000478267	SCV004238616	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113656	SCV000146949	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496350	SCV000587870	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research