Submissions for variant NM_000059.4(BRCA2):c.5238dup (p.Asn1747Ter)

dbSNP: rs80359499

Total submissions: 37

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031535	SCV000300851	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	RCV000257922	SCV000072631	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1747*) 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 and/or ovarian cancer (PMID: 11802209, 16168118, 23110154, 25682074, 26681312). This variant is also known as 5466insT. ClinVar contains an entry for this variant (Variation ID: 37954). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130726	SCV000185615	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	clinical testing	The c.5238dupT pathogenic mutation (also known as p.N1747*), located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 5238. This changes the amino acid from a asparagine to a stop codon within coding exon 10. This mutation has been described in multiple breast and/or ovarian cancer families, including individuals with pre-menopausal and triple negative breast cancer (Frank TS et al. J. Clin. Oncol. 1998 Jul;16(7):2417-25; Meindl A et al. Int. J. Cancer. 2002 Feb;97(4):472-80; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7(5):R728-36; Palma MD et al. Cancer Res. 2008 Sep;68(17):7006-14; Pern F et al. PLoS One. 2012 Oct;7(10):e47993; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Schroeder C et al. Breast Cancer Res. Treat. 2015 Jul;152:129-136). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 5466insT in published literature. 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.
GeneDx	RCV000212240	SCV000210763	pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	Nonsense 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; Reported in association with hereditary breast and/or ovarian cancer (Frank 1998, Meindl 2002, Nanda 2005, Pohlreich 2005, van der Hout 2006, Song 2014, Wong-Brown 2015, Frey 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 24504028, 24728189, 26681312, 27856273, 28495237, 28324225, 32295079, 16168118, 18703817, 22430266, 16234499, 15131399, 16683254, 9667259, 23110154, 27157322, 25682074, 11802209, 28454591, 27930734, 26022348, 30702160, 32719484)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000257922	SCV000219349	pathogenic	Hereditary breast ovarian cancer syndrome	2015-11-06	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031535	SCV000267778	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212240	SCV000296566	pathogenic	not provided	2021-08-16	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In addition, it has been described in individuals with breast cancer and ovarian cancer (PMID: 26681312 (2015), 25682074 (2015), 25186627 (2015), 24728189 (2014), 22430266 (2012)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031535	SCV000327184	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031535	SCV000488096	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-28	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000257922	SCV000588099	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000257922	SCV000694848	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5238dupT (p.Asn1747X) 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 252034 control chromosomes. c.5238dupT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Meindl_2002, Nanda_2005, Palma_2008, Pern_2012, Pohlreich_2005, Song_2014). 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 and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130726	SCV000747811	pathogenic	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130726	SCV000905014	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-06	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. This variant has been reported in at least eight individuals affected with breast or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9667259, 11802209, 16168118, 16234499, 18703817, 23110154, 24504028, 24728189, 25186627, 25682074, 26681312). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170969	SCV001333629	pathogenic	Breast and/or ovarian cancer	2021-11-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262734	SCV001440711	pathogenic	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000212240	SCV001449908	pathogenic	not provided	2017-09-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212240	SCV001716155	pathogenic	not provided	2020-12-07	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212240	SCV001762063	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212240	SCV002010358	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212240	SCV002019086	pathogenic	not provided	2022-11-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496483	SCV002811039	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-02-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212240	SCV004024414	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001262734	SCV004213729	pathogenic	Familial cancer of breast	2023-07-24	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003884336	SCV004698109	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-14	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
All of Us Research Program, National Institutes of Health	RCV000031535	SCV004845790	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	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. This variant has been reported in at least eight individuals affected with breast or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9667259, 11802209, 16168118, 16234499, 18703817, 23110154, 24504028, 24728189, 25186627, 25682074, 26681312). 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031535	SCV005045899	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM2_supporting; PM5_PTC_Strong
Department of Human Genetics, Hannover Medical School	RCV000031535	SCV005091218	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212240	SCV005331119	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Sharing Clinical Reports Project (SCRP)	RCV000031535	SCV000054140	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-05-06	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031535	SCV000146580	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000257922	SCV000587753	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353486	SCV000591954	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asn1747X variant was identified in 3 of 1936 proband chromosomes (frequency: 0.002) from German and Czech individuals or families with breast/ovarian or triple negative breast cancers (Meindl 2002, Pohlreich 2005, Pern 2012). The variant was also identified in dbSNP (ID: rs80359499) “With Pathogenic allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The variant was identified in HGMD, the BIC database (9X with pathogenic clinical importance), and in Clinvitae (3x), the ClinVar database by multiple submitters (the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) as a pathogenic variant, 2X by BIC (both somatic and germline) classification not provided, Invitae, classification not provided, classified as pathogenic by Ambry Genetics, GeneDX and Molecular Diagnostic Laboratory - CHEO ). The c.5238 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1747 and leads to a premature stop codon at position 1747. 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 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.
CZECANCA consortium	RCV001170969	SCV001451857	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212240	SCV001741278	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212240	SCV001972057	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031535	SCV002588883	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532449	SCV004740625	pathogenic	BRCA2-related disorder	2024-06-12	no assertion criteria provided	clinical testing	The BRCA2 c.5238dupT variant is predicted to result in premature protein termination (p.Asn1747*). This variant has been documented to be pathogenic in multiple unrelated individuals with breast or ovarian cancer [Reported in Table III as 5466insT(1747X) in Meindl et al. 2002. PubMed ID: 11802209; reported as c.5238insT in Pern et al. 2012. PubMed ID: 23110154; reported in Table S1 as S1746fs in Cunningham et al. 2014. PubMed ID: 24504028; reported in Suppl Table 1 as c.5237_5238insT (p.S1746fs) in Schroeder et al. 2015. PubMed ID: 26022348]. This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37954/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.