13-32332465-GAA-GA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.994delA(p.Ile332PhefsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,844 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
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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.994delA | p.Ile332PhefsTer17 | frameshift_variant | Exon 10 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.625delA | p.Ile209PhefsTer17 | frameshift_variant | Exon 10 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.994delA | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1440844Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2AN XY: 716018
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -
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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 or family history consistent with pathogenic variants in this gene (Turner 1999, Fackenthal 2012, Kim 2012, Kang 2015, Rebbeck 2018); Not observed at 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 1222delA; This variant is associated with the following publications: (PMID: 10506595, 24156927, 28205045, 28392550, 29446198, 29673794, 31825140, 31002019, 26187060, 24549055, 31026599, 22034289, 22798144, 25863477) -
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
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Variant allele predicted to encode a truncated non-functional protein. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 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 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. -
The c.994delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 994, causing a translational frameshift with a predicted alternate stop codon (p.I332Ffs*17). This alteration has been detected in multiple families with breast and/or ovarian cancer (Turner BC et al, J. Clin. Oncol. 1999 Oct; 17(10):3017-24; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Park B et al. Breast Cancer Res. Treat., 2017 May;163:139-150; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also designated as 1222delA 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
This sequence change creates a premature translational stop signal (p.Ile332Phefs*17) 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 a personal and/or family history of breast and/or ovarian cancer (PMID: 10506595, 22798144, 24549055, 28205045). This variant is also known as 1222delA. ClinVar contains an entry for this variant (Variation ID: 52924). For these reasons, this variant has been classified as Pathogenic. -
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Malignant tumor of breast Pathogenic:1
The p.Ile332PhefsX17 variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80359778) “With Pathogenic allele”, LOVD, the ClinVar database (classified as a pathogenic variant by BIC), the BIC database (3X with clinical importance), and UMD (1X as a causal variant). The p.Ile332PhefsX17 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 332 and leads to a premature stop codon 17 codons downstream. This alteration is then predicted to result in 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 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at