13-32362580-TA-TAA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.7865dupA(p.Asn2622LysfsTer4) variant causes a frameshift change involving the alteration of a 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.7865dupA | p.Asn2622LysfsTer4 | frameshift_variant | Exon 17 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.7496dupA | p.Asn2499LysfsTer4 | frameshift_variant | Exon 17 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.7873dupA | non_coding_transcript_exon_variant | Exon 16 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
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Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 267039). This premature translational stop signal has been observed in individual(s) with breast and bladder cancer (PMID: 28008555). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn2622Lysfs*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). -
Variant summary: BRCA2 c.7865dupA (p.Asn2622LysfsX4) 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 251260 control chromosomes (gnomAD) but has been reported in the literature in a male patient affected with breast/bladder cancer (Pritzlaff _2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.7865dupA pathogenic mutation, located in coding exon 16 of the BRCA2 gene, results from a duplication of A at nucleotide position 7865, causing a translational frameshift with a predicted alternate stop codon (p.N2622Kfs*4). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at