rs80359448
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.4449del(p.Asp1484ThrfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T1483T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.60
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32338803-CA-C is Pathogenic according to our data. Variant chr13-32338803-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 37904.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338803-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32338803-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.4449del | p.Asp1484ThrfsTer2 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.4449del | p.Asp1484ThrfsTer2 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461068Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 726740
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35
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1
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:25
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 30, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 01, 2022 | 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). - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 19, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 27, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 04, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | BRCA2: PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 19, 2019 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 24, 2024 | 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) - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 06, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 23, 2023 | 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. - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 30, 2024 | Criteria applied: PVS1,PM5_STR,PM2_SUP - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | 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. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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