Submissions for variant NM_000059.4(BRCA2):c.7480C>T (p.Arg2494Ter)

gnomAD frequency: 0.00001  dbSNP: rs80358972

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)	RCV000031681	SCV000282443	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.
Invitae	RCV000225750	SCV000073240	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2494*) 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 (rs80358972, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9361038, 16455195, 19656164, 22798144, 23199084, 24312913). It has also been observed to segregate with disease in related individuals. This variant is also known as 7708C>T. ClinVar contains an entry for this variant (Variation ID: 38099). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131084	SCV000186014	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	The p.R2494* pathogenic mutation (also known as c.7480C>T), located in coding exon 14 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7480. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation was originally detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families identified in Finland and has subsequently been reported as a founder mutation in the Finnish population (Vehmanen P et al. Hum. Mol. Genet. 1997 Dec;6:2309-15; Janaviius R. EPMA J. 2010 Sep;1:397-412). It has also been identified in multiple HBOC families of Korean descent (Kang HC et al. Hum. Mutat. 2002 Sep;20:235; Son BH et al. Breast Cancer Res. Treat. 2012 Jun;133:1143-52), as well as in other cohorts of individuals with personal and/or family histories consistent with HBOC (Dutil J et al. Cancer Genet. 2012 May;205:242-8; Park J et al. Ann. Lab. Med. 2016 Mar;36:197-201; Weren RD et al. Hum. Mutat. 2017 Feb;38:226-235; Tedaldi G et al. Oncotarget 2017 Jul;8:47064-47075; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Lee K et al. Invest New Drugs, 2018 Feb;36:163-169; Eoh KJ et al. Cancer Res. Treat. 2018 Jul;50(3):917-925). Of note, this alteration is also designated as 7708C>T 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	RCV000045227	SCV000210426	pathogenic	not provided	2021-01-21	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; Observed in mutliple individuals with BRCA2-related cancers and described as a recurrent variant in both Finnish and Korean hereditary breast and ovarian cancer families (Vehmanen 1997, Seong 2009, Janavicius 2010, Kim, 2012, Kang 2015, Lee 2017, Park 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 7708C>T; This variant is associated with the following publications: (PMID: 26709275, 28351343, 29625052, 21735045, 25525159, 25863477, 25802882, 17100994, 19656164, 22217648, 16455195, 22970155, 22798144, 26187060, 26026974, 24312913, 23091540, 21120943, 25706666, 26733283, 27383479, 9361038, 12204006, 23199084, 26848529, 27488874, 27767231, 28127413, 29084914, 28782087, 28205045, 28802053, 29020732, 29339979, 11251181, 28724667, 28423363, 30702160, 30350268, 30287823, 28111427, 30262796, 29446198, 30720243, 30322717, 30309222, 30736435, 32853339, 32719484, 30787465)
Eurofins Ntd Llc (ga)	RCV000045227	SCV000226199	pathogenic	not provided	2015-03-12	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031681	SCV000267807	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000045227	SCV000296715	pathogenic	not provided	2023-06-15	criteria provided, single submitter	clinical testing	The BRCA2 c.7480C>T (p.Arg2494*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 19656164 (2009), 29339979 (2019), 30736435 (2019), prostate cancer (PMID: 32853339 (2021)), gastric cancer (PMID: 32489267 (2020), and ovarian cancer (PMID: 29084914 (2018)). This variant is also suggested to be a founder mutation for both Korean and Finnish populations (PMIDs: 19656164 (2009) and 9361038 (1997)). The frequency of this variant in the general population, 0.00018 (4/21648 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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	RCV000031681	SCV000327668	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031681	SCV000605694	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477038	SCV000611180	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	2021-11-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000031681	SCV000677697	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131084	SCV000683877	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 15 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 9361038, 16455195, 19656164, 22798144, 23199084, 24312913, 27153395, 28724667, 29020732, 29084914) or pancreatic cancer (PMID: 28782087). This variant is known to be a founder mutation in the Korean and Finnish populations (PMID: 23199084, 24312913). This variant has been identified in 8/251440 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000225750	SCV000916927	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7480C>T (p.Arg2494X) 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 3.2e-05 in 251440 control chromosomes. c.7480C>T has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Kim_2012, Sarantaus_2000, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Fourteen clinical diagnostic laboratories and one expert panel (ENIGMA) 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000031681	SCV001132514	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-11	criteria provided, single submitter	curation
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000225750	SCV001251545	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	research	The BRCA2 c.7480C>T (also known as c.7708C>T) (p.R2494*) nonsense variant has been reported in the heterozygous state in multiple studies of individuals with hereditary breast and/or ovarian cancer (PMID: 15548363; 15117986; 17100994; 16455195; 19656164; 19499246; 22798144; 28724667).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000031681	SCV001422849	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-01-29	criteria provided, single submitter	curation	The p.Arg2494Ter variant in BRCA2 has been reported in at least 23 individuals with breast or ovarian cancer, including 20 Korean and 2 Italian individuals (PMID: 27767231, 26709275, 28423363, 21497495, 29020732), and 1 male individual with pancreatic head adenocarcinoma and liver metastases who has a sister with breast cancer (PMID: 28782087), and has been identified in 0.01848% (4/21648) of European (Finnish) chromosomes, 0.01631% (3/18394) of East Asian chromosomes, and 0.003266% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80358972). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease that is also present in the general population. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 38099). This nonsense variant leads to a premature termination codon at position 2494, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in breast and ovarian cancer. In summary, this variant meets criteria to be classified as pathogenic for heredity susceptibility to breast and ovarian cancer in an autosomal dominant manner based on the predicted impact of the variant and multiple occurrences with pathogenic BRCA2 variants in individuals with breast or ovarian cancer. ACMG/AMP Criteria applied: PVS1, PS4, PM2 (Richards 2015).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000045227	SCV001446555	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000045227	SCV001450149	pathogenic	not provided	2015-06-10	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000031681	SCV002061386	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-27	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2
Sema4, Sema4	RCV000131084	SCV002531859	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000045227	SCV003810445	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031681	SCV003932754	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A pathogenic variant was detected in the BRCA2 gene. This sequence change creates a premature translational stop signal (p.Arg2494*) 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 (rs80358972, gnomAD 0.02%). This premature translational stop signal variant has been reported in the heterozygous state in multiple studies of individuals with hereditary breast and/or ovarian cancer (PMID: 15548363; 15117986; 17100994; 16455195; 19656164; 19499246; 22798144; 28724667) or pancreatic cancer (PMID: 28782087).. This variant is also known as 7708C>T. ClinVar contains an entry for this variant (Variation ID: 38099) submitted by thirty clinical diagnostic laboratories after 2014 and all lab classify this variant as pathogenic . For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003460528	SCV004216078	pathogenic	Familial cancer of breast	2023-06-14	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031681	SCV000054288	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-07	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031681	SCV000147102	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	RCV000225750	SCV000587896	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031681	SCV000592114	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Arg2494X variant was identified in 47 of 6296 proband chromosomes (frequency: 0.007) from Korean and Finnish individuals or families with breast and ovarian cancer and was not identified in 2628 control chromosomes from healthy individuals (Park 2017, Kang 2015, Janavicius 2010). The variant was also identified in the following databases: dbSNP (ID: rs80358972) as "With Likely benign, Pathogenic allele", ClinVar (15x, pathogenic), Clinvitae (6x, pathogenic), LOVD 3.0 (15x, pathogenic), UMD-LSDB (23x, causal, co-occurrence with BRCA2 c.2808_2811delACAA, p.Ala938Profsx21), BIC Database (11x, pathogenic), and ARUP Laboratories (definitely pathogenic). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified by our laboratory in one individual with ovarian cancer. The variant was identified in control databases in 8 of 246212 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 3 of 17248 chromosomes (freq: 0.0002), Finnish in 4 of 22300 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003). The variant was not observed in the African, Other, Latino, European, or Ashkenazi Jewish populations. In a study looking at mRNA transcripts and in silico splicing prediction programs, the mutation was found to have no effect on splicing (Menendez 2012). The c.7480C>T variant leads to a premature stop codon at position 2494 which is predicted to lead to 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	RCV001391218	SCV001593134	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000045227	SCV001742105	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000045227	SCV001953798	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162280	SCV002758138	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031681	SCV004243766	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing