rs80359516
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5482_5486delAAATT(p.Lys1828ValfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.5482_5486delAAATT | p.Lys1828ValfsTer4 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.5113_5117delAAATT | p.Lys1705ValfsTer4 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.5482_5486delAAATT | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
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This variant deletes 5 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 (PMID: 11149425, 26187060, 30287823). 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. -
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Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary breast ovarian cancer syndrome Pathogenic:4
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Variant summary: BRCA2 c.5482_5486delAAATT (p.Lys1828ValfsX4) results in a premature termination codon, 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 251050 control chromosomes (gnomAD). c.5482_5486delAAATT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Kwong_2016, Momozawa_2018, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have cited this variant (after 2014) as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Lys1828Valfs*4) 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 cancer (PMID: 26187060, 30287823). ClinVar contains an entry for this variant (Variation ID: 41553). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 5 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 (PMID: 11149425, 26187060, 30287823). 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.5482_5486delAAATT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 5482 to 5486, causing a translational frameshift with a predicted alternate stop codon (p.K1828Vfs*4). This mutation was reported in a 56 year old Japanese female who underwent exome analysis as a subject ascertained for atherosclerosis phenotypes; she did not meet cancer family history based referral criteria (Johnston JJ, Am. J. Hum. Genet. 2012 Jul; 91(1):97-108). This alteration has also been reported as a pathogenic mutation in cohorts of East Asian individuals (Kwong A et al. J. Med. Genet., 2016 Jan;53:15-23; Momozowa Y et al. Nat Commun 2018 10;9(1):4083). 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. -
Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
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not provided Pathogenic:1
The p.Lys1828ValfsX4 variant was identified in the literature in a French family with hereditary breast or ovarian cancer (Lecarpentier 2012). The variant was also identified in the GeneInsight COGR database (classified as pathogenic by a clinical laboratory); UMD (2X, classified as “causal”); the BIC database (4X, with clinical significance), and the ClinVar database (classified as pathogenic by the Biesecker Laboratory - ClinSeq Project, Sharing Clinical Reports Project, BIC, and Ambry Genetics). The p.Lys1828ValfsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1828 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Gastric cancer Pathogenic:1
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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