Submissions for variant NM_000059.4(BRCA2):c.4284dup (p.Gln1429fs)

dbSNP: rs80359439

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)	RCV000031473	SCV000300733	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	RCV000044387	SCV000072400	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1429Serfs*9) 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 (rs80359439, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11179017, 20373018, 22085629, 24156927, 24728189). This variant is also known as 4510insT and 4512insT. ClinVar contains an entry for this variant (Variation ID: 37892). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000130074	SCV000184901	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	The c.4284dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 4284, causing a translational frameshift with a predicted alternate stop codon (p.Q1429Sfs*9). This mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Koumpis C et al. Hered Cancer Clin Pract. 2011;9:10; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Labidi-Galy SI et al. Clin. Cancer Res. 2018 01;24:326-333; Marchetti C et al. Ann. Surg. Oncol. 2018 Nov;25:3701-3708; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620), an individual with prostate cancer (Pilie PG et al. Cancer. 2017 Oct;123(20):3925-3932), and one individual with medulloblastoma diagnosed in infancy (Waszak SM et al. Lancet Oncol. 2018 06;19:785-798). Of note, this alteration is also designated as 4512insT and 4510insT 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	RCV000160287	SCV000210748	pathogenic	not provided	2023-07-26	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 (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4512dupT; This variant is associated with the following publications: (PMID: 21120943, 27836010, 22085629, 24728189, 22762150, 24156927, 24670361, 20373018, 11179017, 27741520, 29061375, 28657667, 29907814, 26360800, 29753700, 21324516, 21702907, 23942203, 30128899, 29641532, 29084914, 30720243, 31368036, 31336956, 29483665, 31447099, 32846166, 32295079, 32438681, 32719484, 32853339, 32782288, 28888541, 36988593, 36329109, 37179432, 36136896, 35205366, 35463374, 35216584)
Counsyl	RCV000031473	SCV000220993	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-12-29	criteria provided, single submitter	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044387	SCV000271327	pathogenic	Hereditary breast ovarian cancer syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.Gln1429SerfsX9 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers (Risch 2001 PMID:11179017, Zuradelli 2010 PMID:20373018, Zhang 2011 PMID:21324516, Koumpis 2011 PMID:22085629, Caux-Moncoutier 2011 PMID:21120943, Song 2014 PMID:24728189, Pilie 2017 PMID:28657667, Nielsen 2016 PMID:26360800, Palmero 2018 PMID:29907814, Waszak 2018 PMID:29753700, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). 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 1429 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Sept 13, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 37892). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria Applied: PS4_Moderate, PM2_Supporting, PVS1.
Color Diagnostics, LLC DBA Color Health	RCV000130074	SCV000292168	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	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 10 individuals affected with breast and ovarian cancer (PMID: 11179017, 21324516, 22085629, 24728189, 27741520, 29084914, 30128899, 33471991; Leiden Open Variation Database DB-ID BRCA2_001668) and in suspected hereditary breast and ovarian cancer families (PMID: 21120943, 24156927, 29483665). This variant also has been reported in an individual affected with prostate cancer with multiple primary malignancies and another individual affected with medulloblastoma (PMID: 28657667, 29753700). This variant has been identified in 1/244426 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160287	SCV000296728	pathogenic	not provided	2020-01-14	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals affected with breast/ovarian and prostate cancer in the published literature (PMID: 28657667 (2017), 27741520 (2016), 21120943 (2011), 22085629 (2011), 11179017 (2001)). 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	RCV000031473	SCV000327007	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000044387	SCV000693567	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change inserts one nucleotide in exon 11 of the BRCA2 mRNA (c.4284dupT), causing a frameshift after codon 1429 and the creation of a premature translation stop signal 9 amino acid residues later p.(Gln1429Serfs*9). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as 4510insT and 4512insT in the international literature and has been reported in individuals affected with breast and ovarian cancer (PMID: 11179017, 20373018, 22085629, 24156927, 24728189). The mutation database ClinVar contains entries for this variant (Variation ID: 37892).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044387	SCV000694762	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4284dupT (p.Gln1429SerfsX9) 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 247482 control chromosomes (gnomAD). c.4284dupT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Risch_2001, Caux-Moncoutier_2011, Song_2014, Tea_2014, Fernandes_2016). These data indicate that the variant is very likely to be associated with disease. Thirteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031473	SCV000839927	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-01-30	criteria provided, single submitter	clinical testing	This c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patient [PMID: 21120943, 22085629, 24728189] while only observed once in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidences, this c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000160287	SCV001248273	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PS4:Moderate, PM2:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000160287	SCV001716153	pathogenic	not provided	2019-09-21	criteria provided, single submitter	clinical testing	PVS1, PS4_Mod, PM1, PM2, PP5
Genetics Program, Instituto Nacional de Cancer	RCV000044387	SCV002515274	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Human Genetics Bochum, Ruhr University Bochum	RCV000031473	SCV002758600	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-03-08	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PS4, PM1, PM2, PP5
New York Genome Center	RCV000031473	SCV002764542	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-12-28	criteria provided, single submitter	clinical testing	The heterozygous c.4284dup (p.Gln1429SerfsTer9) variant identified in exon 11 (of 27) of the BRCA2 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported in multiple unrelated individuals affected with BRCA2-associated disorders [PMID: 11179017;PMID: 26360800;PMID: 28657667;PMID: 29753700]. This variant has also been reported as pathogenic in the ClinVar database by multiple independent laboratories (Variation ID: 37892). The variant is absent from the gnomAD(v3) database indicating it is an extremely rare allele in the populations represented in that database. Based on the available evidence, the heterozygous c.4284dup (p.Gln1429SerfsTer9) variant identified in the BRCA2 gene is reported as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504842	SCV002814250	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	2022-05-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000160287	SCV003813783	pathogenic	not provided	2023-12-16	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031473	SCV003932726	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	BRCA2 (p.Gln1429fs): This insertion of one nucleotide in BRCA2 is denoted c.4284insT at the cDNA level and p.Gln1429SerfsX9 (Q1429SfsX9) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ATTTTT[insT]CAGA. The duplication causes a frameshift, which changes a Glutamine to a Serine at codon 1429 and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4284insT, previously reported as 4510dupT or 4512dupT using alternate nomenclature. The BRCA2 c.4284insT; p.Gln1429fs variant is reported in the literature in multiple individuals affected with breast or ovarian cancer or that met criteria for hereditary breast and/or ovarian cancer (HBOC) syndrome (Fernandes 2016, Koumpis 2011, Palmero 2018, Risch 2001, Zhang 2011, Zuradelli 2010). This variant is present on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37892). This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004532443	SCV004113445	pathogenic	BRCA2-related disorder	2023-07-27	criteria provided, single submitter	clinical testing	The BRCA2 c.4284dupT variant is predicted to result in a frameshift and premature protein termination (p.Gln1429Serfs*9). This variant (also known as 4512dupT and 4510insT) has been frequently reported in the literature as pathogenic in individuals with a personal and/or family history of breast and ovarian cancer (see, for example, Table 1, Risch et al. 2001. PubMed ID: 11179017; Zuradelli et al. 2010. PubMed ID: 20373018; Table 1, Fernandes et al. 2016. PubMed ID: 27741520). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32912770-A-AT). In ClinVar, this variant has been reviewed by an expert panel and is interpreted as pathogenic by numerous laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/37892/). Truncating variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000031473	SCV004171162	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	not provided
Baylor Genetics	RCV003473173	SCV004211781	pathogenic	Familial cancer of breast	2024-02-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031473	SCV004845297	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-08	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 10 individuals affected with breast and ovarian cancer (PMID: 11179017, 21324516, 22085629, 24728189, 27741520, 29084914, 30128899, 33471991; Leiden Open Variation Database DB-ID BRCA2_001668) and in suspected hereditary breast and ovarian cancer families (PMID: 21120943, 24156927, 29483665). This variant also has been reported in an individual affected with prostate cancer with multiple primary malignancies and another individual affected with medulloblastoma (PMID: 28657667, 29753700). This variant has been identified in 1/244426 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003473173	SCV005368132	pathogenic	Familial cancer of breast	2024-05-07	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
Sharing Clinical Reports Project (SCRP)	RCV000031473	SCV000054078	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031473	SCV000146401	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044387	SCV000587708	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353482	SCV000591899	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gln1429SerfsX9 variant was identified in 3 of 4408 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers (Caux-Moncoutier 2011, Risch 2001, Terabeax 2014). The variant was identified by our laboratory in 1 individual who was unaffected at the time of testing. The variant was also identified in dbSNP (ID: rs80359439 “With pathogenic allele”. The p.Gln1429SerfsX9variant was identified in the Clinvar database and classified as pathogenic by Invitae, Ambry Genetics, GeneDx, BIC and Sharing clinical Reports project. Counsy classified the variant as likely pathogenic. In the BRCA Share UMD database, the variant was identified 14x and classified as causal. The variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dup (p.Gln1756ProfsX74). The BIC database identified the variant 4X with clinical importance and classified as pathogenic. The ARUP laboratory identified the variant 1x and classified it as pathogenic. The p.Gln1429SerfsX9 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1429 and leads to a premature stop codon 9 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 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	RCV001271036	SCV001451853	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031473	SCV002588875	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162269	SCV002758295	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research