13-32333318-A-AT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.1842dup(p.Asn615Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,252 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. I614I) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.1842dup | p.Asn615Ter | frameshift_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1842dup | p.Asn615Ter | frameshift_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1456252Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 724224
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
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, 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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 28, 2019 | The p.Asn615X (c.1842dupT) variant in BRCA2 has been reported in at least 3 individuals with BRCA2-related cancers (Esteban Cardeñosa 2010, BIC database). Additionally, it was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar Variation ID: 51212). This variant was absent from large population studies. The p.Asn615X (c.1842dupT) variant is an insertion of a single nucleotide, creating a premature termination codon at position 57, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2017 | Variant summary: The BRCA2 c.1842dupT (p.Asn615X) 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 is absent in 117182 control chromosomes (ExAC). Multiple publications have cited the variant in affected individuals (e.g., Jimenez_Familial Cancer_2013; Hondow_BMC Cancer_2011). 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 | Nov 08, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51212). This variant is also known as 2070dupT. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20033483). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn615*) 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). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2016 | This duplication of one nucleotide is denoted BRCA2 c.1842dupT at the cDNA level and p.Asn615Ter (N615X) at the protein level. The normal sequence, with the base that is duplicated in braces, is TAAT[T]AACT. The duplication creates a nonsense variant, which changes an Asparagine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 1842dupT, also denoted BRCA2 2070dupT and 2070insT using alternate nomenclature, has been observed in at least one breast/ovarian cancer family (Esteban Cardeñosa 2010). Based on currently available evidence, we consider this variant to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 08, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 25, 2023 | The c.1842dupT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a duplication of T at nucleotide position 1842, causing a translational frameshift with a predicted alternate stop codon (p.N615*). This alteration has been reported in multiple individuals with personal and/or family history of hereditary breast and/or ovarian cancer (Esteban Cardeñosa E et al. Breast Cancer Res. Treat. 2010 May;121:257-60; Ruiz A et al. Biomed Res Int 2014 Jun;2014:542541). Of note, this alteration is also designated as 2070dupT 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 | Oct 03, 2023 | This variant inserts 1 nucleotide in exon 10 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 with a personal or family history of breast and/or ovarian cancer (PMID: 20033483, 23479189, 29446198, 30240327, 31090900, 33403015, 33573335). 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:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 20, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at