rs80359651
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.7419_7420del(p.Cys2473Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,428 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. K2472K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7419_7420del | p.Cys2473Ter | frameshift_variant | 14/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7419_7420del | p.Cys2473Ter | frameshift_variant | 14/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250976Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135692
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461428Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727022
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 15, 2009 | - - |
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 | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 18, 2023 | This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMID: 14574155 (2003), 15955690 (2005), 34326862 (2021), 33471991 (2021), 33471991 (2021)). The frequency of this variant in the general population, 0.000004 (1/250976 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 09, 2017 | Variant summary: The BRCA2 c.7419_7420delTG (p.Cys2473X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/245822 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple publications have cited the variant in affected individuals and indicate the variant is a Dutch founder mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change creates a premature translational stop signal (p.Cys2473*) 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 (rs80359651, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 14574155, 15955690, 16683254, 24285858). This variant is also known as c.7647delTG. ClinVar contains an entry for this variant (Variation ID: 38095). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2022 | The c.7419_7420delTG pathogenic mutation, located in coding exon 13 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7419 to 7420, causing a translational frameshift with a predicted alternate stop codon (p.C2473*). This alteration has been previously identified in multiple individuals and families with early onset breast, ovarian, fallopian tube, and/or primary peritoneal cancer (Piek JM et al. Fam Cancer, 2003;2:73-8; Wárlám-Rodenhuis CC et al. Eur J Cancer, 2005 Jul;41:1409-15). Of note, this alteration is also designated as 7647delTG 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 24, 2020 | This variant deletes 2 nucleotides in exon 14 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 individuals and families affected with hereditary breast and/or ovarian cancer (PMID: 14574155, 15955690, 16683254) and is a common disease-causing mutation in the Dutch population (PMID: 25103822). This variant has been identified in 1/250976 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. - |
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Cys2473* variant was identified in dbSNP (ID: rs80359651) as “With Pathogenic allele”, ClinVar (as pathogenic by ENIGMA, CIMBA, Quest Diagnostics, Erasmus Medical Center, University Medical Center Groningen, Women's College Hospital, COGR, SCRP, and BIC), and LOVD 3.0 (76x as pathogenic). The variant was not identified in UMD-LSDB, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was also reported in the literature as a founder mutation in the Northern Netherlands, however the frequency of this variant in an affected population was not provided (Vos 2014). The c.7419_7420del variant leads to a premature stop codon at position 2473 which is predicted to lead to 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 (HBOC) 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. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 03, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at