rs80359388
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.3545_3546del(p.Phe1182Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.655
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 13-32337898-ATT-A is Pathogenic according to our data. Variant chr13-32337898-ATT-A is described in ClinVar as [Pathogenic]. Clinvar id is 37846.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337898-ATT-A is described in Lovd as [Pathogenic]. Variant chr13-32337898-ATT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.3545_3546del | p.Phe1182Ter | frameshift_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.3545_3546del | p.Phe1182Ter | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152226
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250970Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135628
GnomAD3 exomes
AF:
AC:
5
AN:
250970
Hom.:
AF XY:
AC XY:
2
AN XY:
135628
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461780Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 727178
GnomAD4 exome
AF:
AC:
26
AN:
1461780
Hom.:
AF XY:
AC XY:
13
AN XY:
727178
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74374
GnomAD4 genome
AF:
AC:
1
AN:
152226
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74374
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:31
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 04, 2022 | This BRCA2 variant (rs80359388) is rare (<0.1%) in a large population dataset (5/250970 total alleles; 0.002%; no homozygotes) and has an entry in ClinVar11. This nonsense variant, also known as 3772delTT and 3773delTT, has been reported in multiple unrelated individuals affected with hereditary breast and ovarian cancer. This frameshift variant creates a premature termination codon in exon 11 likely leading to nonsense-mediated decay and lack of protein production. We consider c.3545_3546del to be pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Medical University Innsbruck | Feb 11, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 31, 2014 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This variant deletes 2 nucleotides 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 and in families affected with breast and/or ovarian cancer (PMID: 15131399, 15382066, 20104584, 20694749, 21324516, 24156927, 29084914, 29339979, 33471991; Leiden Open Variation Database DB-ID BRCA2_001009) and in an individual affected with Fanconi anemia with a family history of early-onset breast cancer (PMID: 25381700). This variant has been identified in 5/250970 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. - |
not provided Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2020 | 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 as heterozygous in individuals with a personal and/or family history of BRCA2-related cancers, and as compound heterozygous in an individual with Fanconi anemia (Lubinski 2004, Cavallone 2010, Tea 2014, Belanger 2015, Malric 2015, Shindo 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3772delTT or 3773delTT; This variant is associated with the following publications: (PMID: 20104584, 21952622, 15131399, 25884701, 24156927, 21324516, 26986251, 25381700, 15382066, 20694749, 16905680, 28166811, 28767289, 21568838, 18042939, 17416853, 16825431, 16141007, 15796958, 15197194, 12677558, 9497246, 22430266, 26014432, 26295337, 29339979, 29084914, 30128899, 30609409, 30720243, 31851867, 31409081, 32255556) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 21, 2020 | This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000044 (5/113332 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant is also known as 3773delTT, and it has been reported in individuals affected with breast and/or ovarian cancer (PMID: 25884701 (2015), 21324516 (2011), 20694749 (2010), 20104584 (2010)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | BRCA2: PVS1, PM2, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 25, 2021 | The BRCA2 c.3545_3546delTT; p.Phe1182Ter variant (rs80359388), also known as 3772delTT and 3773delTT, has been reported in multiple individuals and families with breast, ovarian, and/or pancreatic cancer (Belanger 2015, Borg 2010, Cremin 2020, Labidi-Galy 2018, Lubinski 2004, Shindo 2017, Tea 2014). This variant is found on only five chromosomes (5/250970 alleles) in the Genome Aggregation Database. This variant deletes two nucleotides, induces an early termination codon and 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: Belanger MH et al. A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population. J Ovarian Res. 2015 Mar 27;8:1. Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Cremin C et al. Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening. Cancer Med. 2020 Jun;9(11):4004-4013. Labidi-Galy SI et al. Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. Clin Cancer Res. 2018 Jan 15;24(2):326-333. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Shindo K et al. Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382-3390. Tea MK et al. Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. Maturitas. 2014 Jan;77(1):68-72. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This sequence change deletes 2 nucleotide from exon 11 of the BRCA2 mRNA (c.3545_3546delTT), creating a premature translational stop signal at codon 1182 (p.Phe1182*). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant has been reported in the literature in individuals affected with breast and ovarian cancer (PMID: 15131399 24156927, 25884701, 20104584) and is also known as 3772delTT and c.3773delTT. The mutation database ClinVar contains entries for this variant (Variation ID: 37846). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 21, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2022 | The p.Phe1182X variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database (https://research.nhgri.nih.gov/bic/), Lubinski 2004 PMID: 15131399, Borg 2010 PMID: 20104584, Cavallone 2010 PMID: 20694749, Zhang 2011 PMID: 21324516, Finkelman 2012 PMID: 22430266, Tea 2014 PMID: 24156927, Belanger 2015 PMID: 25884701, Polsler 2016 PMID: 26014432, Shindo 2017 PMID: 28767289, Heramb 2018 PMID: 29339979, Labidi-Galy 2018 PMID: 29084914, Cremin 2020 PMID: 32255556). It has also been identified in 0.004% (5/113332) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 1182, 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 autosomal dominant HBOC. Furthermore, the p.Phe1182X variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282379.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PVS1, PS4, PM2_Supporting. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Phe1182*) 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 (rs748852670, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 15131399, 20104584, 24156927, 25884701). This variant is also known as 3772delTT, c.3773delTT, and p.Phe1182Terfs. ClinVar contains an entry for this variant (Variation ID: 37846). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 18, 2021 | Variant summary: BRCA2 c.3545_3546delTT (p.Phe1182X) 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 2e-05 in 250970 control chromosomes. c.3545_3546delTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) 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. - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 28, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Apr 07, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 13, 2023 | This variant deletes 2 nucleotides 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 and in families affected with breast and/or ovarian cancer (PMID: 15131399, 15382066, 20104584, 20694749, 21324516, 24156927, 29084914, 29339979, 33471991; Leiden Open Variation Database DB-ID BRCA2_001009) and in an individual affected with Fanconi anemia with a family history of early-onset breast cancer (PMID: 25381700). This variant has been identified in 5/250970 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 30, 2021 | The c.3545_3546delTT pathogenic mutation (also known as p.F1182*), located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 3545 to 3546. This changes the amino acid from a phenylalanine to a stop codon within coding exon 10. This mutation has been well described in the literature and has been seen in multiple individuals with a personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome, including several French-Canadian families (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Oros KK et al. Int. J. Cancer. 2004 Nov;112:411-9; Simard J et al. J. Med. Genet. 2007 Feb;44:107-21; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Belanger MH et al. J. Ovarian Res. 2015 Mar;8:1; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333). Of note, this alteration is also designated as 3773delTT and 3772delTT 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. - |
Carcinoma of pancreas Pathogenic:1
| Pathogenic, no assertion criteria provided | case-control | CZECANCA consortium | Mar 04, 2021 | - - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 26, 2024 | The BRCA2 c.3545_3546delTT variant is predicted to result in premature protein termination (p.Phe1182*). This variant, also known as 3772delTT and 3773delTT, has been reported in individuals with breast, ovarian, and pancreatic cancer (see for example - Lubinski et al. 2004. PubMed ID: 15131399; Shindo et al. 2017. PubMed ID: 28767289; Labidi-Galy et al. 2018. PubMed ID: 29084914, Table S2; Heramb et al. 2018. PubMed ID: 29339979). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BRCA2 are expected to be pathogenic, and this variant has been classified as pathogenic by an expert panel in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/37846). This variant is interpreted as pathogenic. - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Phe1182X variant has been identified in 4 out of 5086 proband chromosomes (frequency 0.001) in individuals with unilateral, contralateral and familial breast and ovarian cancer phenotype; however no control chromosomes were included in these studies (Lubinski 2004, Borg 2010). It is listed in dbSNP database coming from a “clinical source” (ID#: rs80359388) however no frequency information was provided. The variant was identified in ClinVar from 6 sources in at least 23 individuals from different ethnic backgroungs (GeneDx, BIC, Ambry, and SCRP derived from Myriad reports all classify this variant as pathogenic; Counsyl classified this variant as Likely pathogenic). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence and leads to a premature stop codon at position 1182. This alteration is predicted to cause a truncated or absent BRCA2 protein product and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism in familial breast and ovarian cancer patients. In summary, based on the above information, this variant is classified as pathogenic. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at