Submissions for variant NM_000059.4(BRCA2):c.3975_3978dup (p.Ala1327fs)

dbSNP: rs397515636

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000210997	SCV000300692	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	RCV000044327	SCV000072340	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala1327Cysfs*4) 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 (rs764689249, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with breast cancer and breast and ovarian cancer (PMID: 10978364, 16168118, 20104584, 22923021, 25066507, 25366421). This variant is also known as 4206insTGCT. ClinVar contains an entry for this variant (Variation ID: 51578). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000129632	SCV000184425	pathogenic	Hereditary cancer-predisposing syndrome	2025-01-11	criteria provided, single submitter	clinical testing	The c.3975_3978dupTGCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of TGCT at nucleotide position 3975, causing a translational frameshift with a predicted alternate stop codon (p.A1327Cfs*4). This mutation has been reported in multiple breast, ovarian, and prostate cancer patients in the literature (e.g. Plaschke J et al. J. Med. Genet. 2000 Sep;37:E17; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36; Risch HA et al. J. Natl. Cancer Inst. 2006 Dec;98:1694-706; Ratajska M et al. J. Appl. Genet. 2015 May;56:193-8; Na R et al. Eur. Urol. 2017 05;71(5):740-747; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620), including male breast cancer patients (e.g. Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Strojnik K et al. Breast Cancer Res Treat, 2021 Aug;188:811-820). Of note, this mutation is also designated as 4206ins4 and 4203_4206dupTGCT 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000210997	SCV000267763	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486384	SCV000296573	pathogenic	not provided	2024-11-17	criteria provided, single submitter	clinical testing	The BRCA2 c.3975_3978dup (p.Ala1327Cysfs*4) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with pancreatic cancer (PMID: 32073954 (2020)), ovarian cancer (PMID: 36367610 (2023), 35382848 (2022), 30441849 (2018)), male breast cancer (PMID: 33891299 (2021), 28008555 (2017)), and breast cancer (PMID: 10978364 (2000), 29907814 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
GeneKor MSA	RCV000238801	SCV000296821	pathogenic	Familial cancer of breast	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change is a duplication of 4 nucleotides in exon 11 of BRCA2 mRNA (c3975_3978dupTGCT), causing a frameshift after codon 1327 and the creation of a premature translation stop signal 4 amino acid residues later (p.Ala1327Cysfs*4). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular variant has been reported in international bibliography in breast and ovarian cancer patients (PMID: 25366421; PMID: 10978364 The mutation database ClinVar contains an entry for this variant (Variation ID: 51578). This variant is also known as 4206insTGCT in the literature using alternative nomenclature.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000210997	SCV000326951	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486384	SCV000566285	pathogenic	not provided	2023-06-07	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Plaschke et al., 2000; Lubinski et al., 2004; Pohlreich et al., 2005; Borg et al., 2010; Stegel et al., 2011; Zhang et al., 2011; Novakovic et al., 2012; Karami et al., 2013; Janavicius et al., 2014; Krajc et al., 2014; Ratajska et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4203_4206dupTGCT, 3978insTGCT, and 4206insTGCT; This variant is associated with the following publications: (PMID: 26689913, 31447099, 20104584, 25066507, 29907814, 31159747, 29922827, 30040829, 16168118, 10978364, 21324516, 21232165, 15131399, 26315209, 24312913, 28008555, 22923021, 25366421, 29101607, 27989354, 29161300, 30720243, 29945567, 29625052, 33891299, 35382848, 35409996, 23397983)
Color Diagnostics, LLC DBA Color Health	RCV000129632	SCV000683594	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-29	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4206ins4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 20 individuals affected with breast cancer, including 7 male individuals, and 5 individuals affected with ovarian cancer (PMID: 10978364, 16168118, 17148771, 17997147, 18824701, 20104584, 21324516, 25066507, 25330149, 25366421, 28008555, 29161300, 30441849, 33471991; Leiden Open Variation Database DB-ID BRCA2_002096, 33891299, 34949660). This variant has been reported in several hereditary breast and ovarian cancer families (PMID: 21232165, 22923021, 23397983, 29907814, 31409081) and has been identified in 10 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/225036 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	RCV000044327	SCV000694733	pathogenic	Hereditary breast ovarian cancer syndrome	2020-07-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3975_3978dupTGCT (p.Ala1327CysfsX4) 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 229858 control chromosomes (gnomAD). c.3975_3978dupTGCT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (e.g. Plaschke_2000, Pohlreich_2005, Brozek_2007, Spearman_2008, Borg_2010, Zhang_2011, Novakovic_2012, Krajc_2014, 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. 11 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them 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	RCV000210997	SCV000839906	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-03	criteria provided, single submitter	clinical testing	This c.3975_3978dup (p.Ala1327Cysfs*4) has previously been reported in at least two patients from two cohorts of 134 and 40 patients respectively [PMID 25366421, 10978364, reported as 4206insTGCT in the latter]. The c.3975_3978dup (p.Ala1327Cysfs*4) variant has been observed in one European (Non Finnish) individual at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/13-32912466-C-CTGCT). This 4 bp duplication is located in exon 11, and leads to the creation of a frameshift and a premature stop codon at amino acid position 1330 of the BRCA2 protein. It is thus classified as pathogenic. This variant is also considered medically actionable [ACMG59, PMID 27854360].
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000210997	SCV001368695	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-12-09	criteria provided, single submitter	research	PVS1, PS4_STR PM2_SUP
Institute of Human Genetics, University of Leipzig Medical Center	RCV000210997	SCV001428535	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-12-02	criteria provided, single submitter	clinical testing
Institute of Genomics, University of Tartu	RCV000210997	SCV001430700	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	research
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000486384	SCV001450246	pathogenic	not provided	2014-10-10	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310147	SCV001499725	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000486384	SCV002010373	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288544	SCV002580405	pathogenic	Malignant tumor of prostate	2021-09-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV002294004	SCV002587078	pathogenic	Breast carcinoma	2022-10-05	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4, PM2_SUP
Revvity Omics, Revvity	RCV000486384	SCV003812497	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000238801	SCV004210346	pathogenic	Familial cancer of breast	2023-04-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000210997	SCV004845252	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-22	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4206ins4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 20 individuals affected with breast cancer, including 7 male individuals, and 5 individuals affected with ovarian cancer (PMID: 10978364, 16168118, 17148771, 17997147, 18824701, 20104584, 21324516, 25066507, 25330149, 25366421, 28008555, 29161300, 30441849, 33471991; Leiden Open Variation Database DB-ID BRCA2_002096, 33891299, 34949660). This variant has been reported in several hereditary breast and ovarian cancer families (PMID: 21232165, 22923021, 23397983, 29907814, 31409081) and has been identified in 10 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 1/225036 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	RCV000044327	SCV004848650	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-20	criteria provided, single submitter	clinical testing	The p.Ala1327CysfsX4 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers, including 7 males (2 prostate; 5 breast cancer; Plaschke 2000 PMID: 10978364, Lu 2015 PMID: 26689913, Ratajska 2015 PMID: 25366421, Alemar 2017 PMID: 29161300, Na 2017 PMID: 27989354, Huang 2018 PMID: 29625052, Palmero 2018 PMID: 29907814, Young 2018 PMID: 29945567, Tsaousis 2019 PMID: 31159747, Strojnik 2021 PMID: 33891299). 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 1327 and leads to a premature termination codon 4 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 autosomal dominant hereditary breast and ovarian cancer (BRCA2). Additionally, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51578). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Moderate.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001310147	SCV005368512	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-06-24	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM5_STR,PM2_SUP
CeGaT Center for Human Genetics Tuebingen	RCV000486384	SCV005909643	pathogenic	not provided	2025-03-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PS4:Moderate, PM2:Supporting
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044327	SCV000587692	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000210997	SCV001551160	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Ala1327Cysfs*4 variant was identified in 12 of 3586 proband chromosomes (frequency: 0.003) from European (Slovenian, Czech and Polish) individuals or families with breast and ovarian cancer and male individuals with breast cancer; and was not identified in 80 control chromosomes from healthy individuals (Pohlreich 2005, Stegel 2011, Pritzaff 2016, Novakovic 2012, Ratajska 2015). The variant was also identified in dbSNP (ID: rs764689249) as “NA”, ClinVar (classified pathogenic, reviewed by an expert panel (2019); submitters: ENIGMA, Invitae, Ambry Genetics, GeneDx, and 8 other laboratories), and LOVD 3.0 (1x). The variant was not identified in UMD-LSDB (unavailable) or in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3975_3978dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1327 and leads to a premature stop codon at position 1331. 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.
BRCAlab, Lund University	RCV000210997	SCV002588870	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Medical Genetics, Medical University Pleven	RCV000210997	SCV004100895	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	research