Submissions for variant NM_000059.4(BRCA2):c.5213_5216del (p.Thr1738fs)

dbSNP: rs80359493

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031532	SCV000300845	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044609	SCV000072622	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1738Ilefs*2) 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 (rs753870552, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11920643, 16683254, 19949876, 24156927, 24504028, 26659639, 27831900). This variant is also known as 5439delTACT. ClinVar contains an entry for this variant (Variation ID: 37951). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000234881	SCV000273746	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-07	criteria provided, single submitter	clinical testing	The c.5213_5216delCTTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5213 to 5216, causing a translational frameshift with a predicted alternate stop codon (p.T1738Ifs*2). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Tea MK et al. Maturitas. 2014 Jan;77:68-72; Francies FZ et al. BMC Cancer. 2015 Nov;15:912; Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Wen WX et al. J Med Genet, 2018 02;55:97-103). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (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.
Color Diagnostics, LLC DBA Color Health	RCV000234881	SCV000292170	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-29	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 also known as 5441delCTTA, 5439del4 and 5439delTACT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in at least ten individuals affected with breast and/or ovarian cancer (PMID: 19949876, 22923021, 24728189, 28993434, 31076742 , 35464868) and multiple hereditary breast and ovarian cancer families (PMID: 11920643, 16683254, 24156927, 29446198 ). This variant has been identified in 1/248142 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031532	SCV000327171	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486732	SCV000568472	pathogenic	not provided	2021-12-17	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 at significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5441_5444delCTTA; This variant is associated with the following publications: (PMID: 26295337, 28814288, 26689913, 11920643, 24728189, 26659639, 22923021, 24156927, 26577449, 24504028, 21305653, 16683254, 16615107, 18489799, 27831900, 28724667, 28993434, 30720243, 29625052, 31825140, 30787465)
Genologica Medica	RCV000031532	SCV000577955	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-01	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000486732	SCV000693571	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes four nucleotides from exon 11 of the BRCA2 mRNA (c.5213_5216delCTTA), causing a frameshift after codon 1738 and the creation of a premature translational stop signal 2 amino acid residues later p.(Thr1738Ilefs*2). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular sequence change has been reported in individuals with breast and/or ovarian cancer (PMID: 11920643, 24504028). This variant is also known as 5439delTACT in the literature. The mutation database ClinVar contains entries for this variant (Variation ID: 37951).
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031532	SCV000744465	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000044609	SCV000838808	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486732	SCV000887845	pathogenic	not provided	2020-11-23	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in multiple individuals with hereditary breast and/or ovarian cancer in the published literature (PMID: 29625052 (2018), 28814288 (2017), 27831900 (2016), 26659639 (2016), 26577449 (2015), 24728189 (2014), 24156927 (2014), 24504028 (2014), 22923021 (2012), 11920643 (2002)). Based on the available information, this variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000486732	SCV001248276	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310156	SCV001499734	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044609	SCV001623167	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5213_5216delCTTA (p.Thr1738IlefsX2) 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 allele was found at a frequency of 4e-06 in 251212 control chromosomes. c.5213_5216delCTTA has been widely 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. 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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044609	SCV002026111	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000031532	SCV002579503	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-07-19	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV002463621	SCV002758614	pathogenic	Pancreatic cancer, susceptibility to, 2	2021-11-10	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PM2, PS4
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000486732	SCV002761165	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000234881	SCV004034092	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-01	criteria provided, single submitter	research
Baylor Genetics	RCV003473183	SCV004211877	pathogenic	Familial cancer of breast	2024-02-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492313	SCV004240322	pathogenic	Breast and/or ovarian cancer	2023-06-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031532	SCV004845784	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-11	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 also known as 5441delCTTA, 5439del4 and 5439delTACT in the literature. 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 observed in at least three individuals affected with breast and/or ovarian cancer (PMID: 19949876, 22923021, 24728189) and multiple hereditary breast and ovarian cancer families (PMID: 11920643, 16683254, 24156927). This variant has been identified in 1/248142 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044609	SCV004848399	pathogenic	Hereditary breast ovarian cancer syndrome	2020-06-19	criteria provided, single submitter	clinical testing	The p.Thr1738IlefsX2 variant in BRCA2 has been reported in at least 50 individuals with BRCA2-related cancer (first reported in: van der Hout 2006 PMID: 16683254). It has also been identified in 1/112458 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as pathogenic on 09/08/16 by the ClinGen-approved ENIGMA expert panel (Variation ID 37951). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1738 and leads to a premature termination codon 2 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 (HBOC). Two other variants, c.5212dup and c.5213del, both resulting in the same amino acid change have been identified in individuals with HBOC and are classified as pathogenic in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS1, PM2, PS4.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000486732	SCV005199507	pathogenic	not provided	2024-02-16	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031532	SCV000054137	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-08-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031532	SCV000146567	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044609	SCV000587749	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031532	SCV000733263	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000486732	SCV001906202	pathogenic	not provided		no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128131	SCV003804354	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031532	SCV004243657	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732566	SCV005354729	pathogenic	BRCA2-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The BRCA2 c.5213_5216delCTTA variant is predicted to result in a frameshift and premature protein termination (p.Thr1738Ilefs*2). Also known in the literature as 5439delTACT, this variant has been reported in individuals with breast and/or ovarian cancer (Montagna et al. 2002. PubMed ID: 11920643; Table S1 in Cunningham et al. 2014. PubMed ID: 24504028; Natarajan et al. 2016. PubMed ID: 27831900). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been interpreted as pathogenic by an expert review panel in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/37951/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.