13-32339568-CTTAT-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5217_5220del(p.Tyr1739Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,674 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. T1738T) 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.5217_5220del | p.Tyr1739Ter | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5217_5220del | p.Tyr1739Ter | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1456674Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 724684
GnomAD4 genome Cov.: 33
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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2017 | Variant summary: The BRCA2 c.5217_5220delTTTA (p.Tyr1739fs) 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. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, it seems to be in a mutation hot spot, where other pathogenic variants have been reported such as c.5218_5223del7, c.5213_5216del4, and c.5217_5221del5. 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 | Apr 14, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51820). This variant is also known as 5445del4. This premature translational stop signal has been observed in individual(s) with prostate cancer, ovarian cancer, or breast cancer (PMID: 9150154, 10717622, 11802209, 12872265, 26681312). This sequence change creates a premature translational stop signal (p.Tyr1739*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 20, 2017 | The p.Tyr1739X variant in BRCA2 has been reported 5 individuals with BRCA2-assoc iated cancers (Stuppia 2003, Susswein 2015, Breast Cancer Information Core (BIC) ). It was also absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This nonsense variant is a result of a deletion of 4 bases, which creates a premature termination codon at position 1739. This alteration is then predicted to lead to a truncated or absen t protein. Heterozygous loss of function of the BRCA2 gene is an established dis ease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as pathogenic on September 8, 2016 by the ClinGen-approv ed ENIGMA expert panel (ClinVar SCV000300847.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on predicted impact to the protein and absence from controls. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2021 | The c.5217_5220delTTTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5217 to 5220, causing a translational frameshift with a predicted alternate stop codon (p.Y1739*). This alteration has identified in individuals diagnosed with prostate cancer, ovarian cancer and breast cancer (Stuppia L et al. Hum Mutat. 2003 Aug;22(2):178-9; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; De Talhouet S et al. Sci Rep, 2020 04;10:7073). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this mutation is also designated as 5445del4 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 | Apr 04, 2023 | This variant deletes 4 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 individuals affected with breast cancer (Color data), ovarian cancer (PMID: 26681312) and prostate cancer (PMID: 12872265). 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2022 | 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 in individuals with a personal or family history consistent with pathogenic variants in this gene (Stuppia 2003, Carter 2018); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5445_5448delTTTA and 5445del4; This variant is associated with the following publications: (PMID: 12872265, 26681312, 30322717, 31447099) - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at