13-32333238-CAAATA-CA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.1763_1766delATAA(p.Asn588SerfsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,460,078 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
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.1763_1766delATAA | p.Asn588SerfsTer25 | frameshift_variant | Exon 10 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.1394_1397delATAA | p.Asn465SerfsTer25 | frameshift_variant | Exon 10 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.1763_1766delATAA | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460078Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726336
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
- -
Variant allele predicted to encode a truncated non-functional protein. -
- -
- -
Hereditary breast ovarian cancer syndrome Pathogenic:4
This sequence change creates a premature translational stop signal (p.Asn588Serfs*25) 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 premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 12942367, 20960228, 25415331). This variant is also known as 1991delATAA, and 1991del4. ClinVar contains an entry for this variant (Variation ID: 51187). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.1763_1766delATAA (p.Asn588SerfsX25) results in a 4 nucleotides deletion from exon 10, causing a frameshift which results in a premature termination codon. This is 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 was absent in 251676 control chromosomes (gnomAD). The variant, c.1763_1766delATAA, has been reported in the literature in many individuals and several families affected with Hereditary Breast And Ovarian Cancer Syndrome (example Laitman_2011, Dobricic_2013, Tea_2014, Torres_2017, Yang_2017, George_2021, Figlioli_2021). These data indicate that the variant is very likely to be associated with disease. Ten submissions have been made to ClinVar after 2014 assessing the variant and all classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
- -
The p.Asn588fs variant in BRCA2 has been reported in 7 individuals with BRCA2-as sociated cancers (Laitman 2011, Kanaan 2003, Dobricic 2013, Breast Cancer Inform ation Core (BIC) database) and was absent from large population studies. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 588 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the BRCA2 gene is an estab lished disease mechanism in individuals with hereditary breast and ovarian cance r (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300460.2). In s ummary, the p.Asn588fs variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls and t he predicted impact to the protein. -
not provided Pathogenic:3
The BRCA2 c.1763_1766del (p.Asn588Serfs*25) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 36605468 (2023), 35641219 (2022), 33646313 (2021), 28680148 (2017), 28664506 (2017), 27469594 (2016), 25415331 (2014), 24156927 (2014), 23635950 (2013), 20960228 (2011), 12942367 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
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 and/or family history consistent with pathogenic variants in this gene (Kanaan et al., 2003; Laitman et al., 2011; Donenberg et al., 2016; Torres et al., 2017; Yang et al., 2017); Not observed at significant frequency 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 1991del4 and 1991_1994del; This variant is associated with the following publications: (PMID: 20960228, 24156927, 27469594, 12942367, 23635950, 28664506, 28918466, 28680148, 28828701, 31159747, 31921681, 33646313, 30875412, 30787465, 33632156, 30541753, 25415331) -
The BRCA2 c.1763_1766delATAA; p.Asn588fs (traditionally known as 1991_1994del4) is published in the medical literature in individuals and families with breast cancer (Kanaan 2003, Torres 2017). The variant is listed in the ClinVar database (Variation ID: 51187), in the dbSNP variant database (rs80359303), but not in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The variant deletes four nucleotides, results in a premature termination codon, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Kanaan Y et al. Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases. Hum Genet. 2003 Oct;113(5):452-60. Torres D et al. Prevalence and Penetrance of BRCA1 and BRCA2 Germline Mutations in Colombian Breast Cancer Patients. Sci Rep. 2017 Jul 5;7(1):4713. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.1763_1766delATAA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1763 to 1766, causing a translational frameshift with a predicted alternate stop codon (p.N588Sfs*25). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) families (Kanaan Y et al. Hum Genet. 2003 Oct;113(5):452-60; Dobrii J et al. J Hum Genet. 2013 Aug;58(8):501-7; Laitman Y et al. Breast Cancer Res Treat. 2011 Jun;127(2):489-95; Tea M et al Maturitas. 2014 Jan;77(1):68-72; Bolognesi C et al. PLoS One, 2014 Nov;9:e112354; Donenberg T et al. Breast Cancer Res Treat, 2016 08;159:131-8; Torres D et al. Sci Rep. 2017 Jul;7:4713; Yang XR et al. Breast Cancer Res. Treat. 2017 Oct;165:687-697; Ow SGW et al. PLoS One, 2019 Mar;14:e0213746; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 1991delATAA 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. -
This variant deletes 4 nucleotides 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 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. -
BRCA2-related cancer predisposition Pathogenic:1
- -
Familial cancer of breast Pathogenic:1
This variant is a 4 bp deletion at amino acid residue 588 of the BRCA2 gene. It results in a frame-shift creating an unrecognizable protein after amino acid 588 and a new stop codon 25 amino acid residues later, thus resulting in a truncated protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at