Submissions for variant NM_000059.4(BRCA2):c.6059_6062del (p.Glu2020fs)

dbSNP: rs398122546

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000076952	SCV000300974	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000076952	SCV000327342	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000076952	SCV000605685	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496781	SCV000635489	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu2020Valfs*19) 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 breast cancer (PMID: 15951958, 28637432). ClinVar contains an entry for this variant (Variation ID: 91435). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000562084	SCV000661171	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-04	criteria provided, single submitter	clinical testing	The c.6059_6062delAACA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 6059 to 6062, causing a translational frameshift with a predicted alternate stop codon (p.E2020Vfs*19). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in 4 families (Heramb C. et al. Hered Cancer Clin Pract. 2018 Jan;16:3). 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.
Color Diagnostics, LLC DBA Color Health	RCV000562084	SCV000683751	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-24	criteria provided, single submitter	clinical testing	This variant deletes 4 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 2 individuals affected with breast cancer (PMID: 28637432, 33471991; Leiden Open Variation Database DB-ID BRCA2_000694) and has been identified in 6 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.
GeneDx	RCV000657383	SCV000779116	pathogenic	not provided	2017-09-07	criteria provided, single submitter	clinical testing	This deletion of four nucleotides in BRCA2 is denoted c.6059_6062delAACA at the cDNA level and p.Glu2020ValfsX19 (E2020VfsX19) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 6287_6290delAACA. The normal sequence, with the bases that are deleted in brackets, is AACG[delAACA]TTCA. The deletion causes a frameshift which changes a Glutamic Acid to a Valine at codon 2020, and creates a premature stop codon at position 19 of the new reading frame. This variant has been observed in at least one case of early-onset breast cancer (Grindedal 2017) and it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000657383	SCV001449925	pathogenic	not provided	2018-05-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496781	SCV001774613	pathogenic	Hereditary breast ovarian cancer syndrome	2021-08-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6059_6062delAACA (p.Glu2020ValfsX19) 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 250910 control chromosomes. c.6059_6062delAACA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very 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 consotrium (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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496781	SCV004848284	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Glu2020ValfsX19 variant in BRCA2 has been reported in at least 6 families with breast cancer (Heramb 2018, Bergman 2005, Grindedal 2017). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2020 and leads to a premature termination codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 91435). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000657383	SCV005199530	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000657383	SCV005414155	pathogenic	not provided	2024-06-10	criteria provided, single submitter	clinical testing	PM2, PM5_strong, PVS1
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV005237513	SCV005882941	pathogenic	Inherited breast cancer and ovarian cancer	2024-10-08	criteria provided, single submitter	clinical testing	PVS1,PM5_Strong
Sharing Clinical Reports Project (SCRP)	RCV000076952	SCV000108749	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-03-05	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496781	SCV000587820	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353772	SCV000592025	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Glu2020ValfsX19 deletion was not identified in the literature but has been reported 1x in the UMD database as causal. This deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2020 and leads to a premature stop codon 19 codons downstream. 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. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.
BRCAlab, Lund University	RCV000076952	SCV002588898	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing