Submissions for variant NM_000059.4(BRCA2):c.6079dup (p.Arg2027fs)

dbSNP: rs397507826

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000076953	SCV000282420	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000132018	SCV000187077	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	The c.6079dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 6079, causing a translational frameshift with a predicted alternate stop codon (p.R2027Kfs*22). This alteration has been described in numerous breast and ovarian cancer cohorts (Evans DG et al. Fam. Cancer. 2008 Jul;7(2):113-117; Song H et al. Hum. Mol. Genet. 2014 Sep;23(17):4703-4709; Copson ER et al. Lancet Oncol. 2018 02;19(2):169-180; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000076953	SCV000327347	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000076953	SCV000488035	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508580	SCV000600678	pathogenic	not provided	2017-03-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496519	SCV000694935	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6079dupA (p.Arg2027LysfsX22) 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. The variant allele was found at a frequency of 4e-06 in 250972 control chromosomes (gnomAD). c.6079dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And/or Ovarian Cancer (examples: Spearman_2008, Evans_2008, Song_2014, Castera_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18824701, 17636422, 24728189, 24549055). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770730	SCV000902211	pathogenic	Breast and/or ovarian cancer	2017-09-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132018	SCV000911765	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-07	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 17636422, 21120943, 24549055, 24728189, 27153395). This variant has been identified in 1/250972 chromosomes 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	RCV000496519	SCV001591686	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2027Lysfs*22) 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 present in population databases (rs749927339, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 14574168, 21120943, 24728189). This variant is also known as 6308insA. ClinVar contains an entry for this variant (Variation ID: 52005). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000076953	SCV000108750	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496519	SCV000587822	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research