Submissions for variant NM_000059.4(BRCA2):c.4449del (p.Asp1484fs)

dbSNP: rs80359448

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031485	SCV000300747	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.
GeneDx	RCV000412671	SCV000210751	pathogenic	not provided	2024-04-24	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 (PMID: 11802209, 15744030, 20104584, 25111659, 27767231, 34326862); 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 4677delA; This variant is associated with the following publications: (PMID: 16683254, 17403394, 24285858, 32073954, 11802209, 25111659, 18403564, 26681312, 21305653, 27226433, 20104584, 15744030, 15131399, 16684319, 27767231, 28873162, 29791287, 31589614, 28888541, 31076742, 33287145, 29053726, 29446198, 34326862, 34242281, 33471991, 37732318, 37506692)
Ambry Genetics	RCV000163360	SCV000213896	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-04	criteria provided, single submitter	clinical testing	The c.4449delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 4449, causing a translational frameshift with a predicted alternate stop codon (p.D1484Tfs*2). This mutation has been reported in multiple familial breast, ovarian, and prostate cancer kindreds to date (Meindl A et al. Int. J. Cancer 2002 Feb;97:472-80; Leegte B et al. J. Med. Genet. 2005 Mar;42:e20; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Maier C et al. Prostate 2014 Oct;74:1444-51; Weren RD et al. Hum. Mutat. 2017 Feb;38(2):226-235). Of note, this alteration is also designated as 4677delA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031485	SCV000327035	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031485	SCV000488692	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163360	SCV000688876	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This variant deletes 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 five individuals affected with breast, ovarian or prostate cancer (PMID: 20104584, 25111659, 27767231, 29053726, 33471991; Leiden Open Variation Database DB-ID BRCA2_001679; Color internal data), in several suspected hereditary breast and ovarian cancer families (PMID: 11802209, 16683254, 29446198), and in one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001679). 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031485	SCV000744455	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000412671	SCV000887818	pathogenic	not provided	2019-07-19	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition it has been reported in individuals affected with ovarian cancer, prostate cancer, and breast cancer in the published literature (PMID: 27767231 (2017), 25111659 (2014), 20104584 (2010), 15744030 (2005)). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000412671	SCV001470860	pathogenic	not provided	2023-09-04	criteria provided, single submitter	clinical testing	The BRCA2 c.4449del; p.Asp1484ThrfsTer2 variant (rs80359448), also known as 4677delA, is reported in the literature in multiple individuals and families affected with breast, ovarian, or prostate cancer (Harter 2017, Maier 2014, Meindl 2002, Vos 2019, Weren 2017). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 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. References: Harter P et al. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). PLoS One. 2017 Oct 20;12(10):e0186043. PMID: 29053726. Maier C et al. Subgroups of familial and aggressive prostate cancer with considerable frequencies of BRCA2 mutations. Prostate. 2014 Oct;74(14):1444-51. PMID: 25111659. Meindl A et al. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002 Feb 1;97(4):472-80. PMID: 11802209. Vos JR et al. Universal tumor DNA BRCA1/2 testing of ovarian cancer: prescreening PARPi treatment and genetic predisposition. J Natl Cancer Inst. 2019 May 11. pii: djz080. PMID: 31076742. Weren RD et al. Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas. Hum Mutat. 2017 Feb;38(2):226-235. PMID: 27767231.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496426	SCV001577944	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1484Thrfs*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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is also known as c.4677delA, 1485* and T1483fs. ClinVar contains an entry for this variant (Variation ID: 37904). For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000163360	SCV002533872	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000031485	SCV002556648	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-03-01	criteria provided, single submitter	clinical testing	The BRCA2:c.4449del variant is classified as PATHOGENIC (ENIGMA criteria 2017) BRCA2:c.4449del is a single nucleotide deletion in exon 11 predicted to encode a frame-shift in translation of the mature mRNA with consequent premature termination of protein synthesis at codon 2 of the frame-shift, or 1485 (BRCA2:p.(Asp1484ThrfsTer2) using NP_000050.3. This is predicted to result in absent BRCA2 protein due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic. This variant has been reviewed by the ENIGMA expert review panel: ENIGMA determine BRCA2:c.4449del as consistent with an IARC Class 5 variant equivalent to ACMG classification of Pathogenic. This variant is also reported in the literature as BRCA2 4677delA using legacy nomenclature. BRCA2:c.4449del has been reported in multiple unrelated individuals with breast, prostate, or ovarian cancer (Meindl et al., 2002, PMID:11802209, Borg et al., 2010, PMID:20104584, Weren et al., 2017, PMID:27767231, Maier et al., 2014, PMID:25111659). BRCA2:c.4449del (rs80359448) is absent from population databases and is not on record in FLOSSIES. BRCA2:c.4449del is on record in ClinVar (Variation ID:37904) reported by multiple clinical laboratories without conflict as pathogenic in association with hereditary breast and ovarian cancer syndrome. This variant is listed in HGMD as ‘disease causing mutation’ in association with breast and/or ovarian cancer (Accession:CD021793).
MGZ Medical Genetics Center	RCV000031485	SCV002579083	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-05-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000412671	SCV002822068	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2
Revvity Omics, Revvity	RCV000412671	SCV003810434	pathogenic	not provided	2023-10-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473176	SCV004210423	pathogenic	Familial cancer of breast	2023-01-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031485	SCV004845682	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-02	criteria provided, single submitter	clinical testing	This variant deletes 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 five individuals affected with breast, ovarian or prostate cancer (PMID: 20104584, 25111659, 27767231, 29053726, 33471991; Leiden Open Variation Database DB-ID BRCA2_001679; Color internal data), in several suspected hereditary breast and ovarian cancer families (PMID: 11802209, 16683254, 29446198), and in one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001679). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003473176	SCV005368368	pathogenic	Familial cancer of breast	2024-07-30	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR,PM2_SUP
Sharing Clinical Reports Project (SCRP)	RCV000031485	SCV000054090	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-03-19	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031485	SCV000146423	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	RCV000496426	SCV000587713	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031485	SCV000733256	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785220	SCV000923788	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000412671	SCV001905712	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412671	SCV001952683	pathogenic	not provided		no assertion criteria provided	clinical testing