rs1555281357
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000059.4(BRCA2):c.672_681+23delTACTACTGCTGTAAGTAAATATGACATTGATTA(p.Asp224HisfsTer3184) variant causes a frameshift, splice donor, splice region, intron 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 Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift, splice_donor, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.671_681+22delATACTACTGCTGTAAGTAAATATGACATTGATT | p.Asp224HisfsTer3184 | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | Exon 8 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.302_312+22delATACTACTGCTGTAAGTAAATATGACATTGATT | p.Asp101HisfsTer3184 | frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant | Exon 8 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.671_681+22delATACTACTGCTGTAAGTAAATATGACATTGATT | splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant | Exon 7 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:1
This variant results in the deletion of part of exon 8 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 462411). For these reasons, this variant has been classified as Pathogenic. -
not provided Uncertain:1
In-frame transcript, E6Q39_E8, able to complement growth in mouse embryonic stem cells, leading to homology-directed repair activity comparable to wild-type (PMID: 32398771); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32398771) -
Hereditary cancer-predisposing syndrome Uncertain:1
The c.672_681+23DEL33 variant results from a deletion of 33 nucleotides starting at position 672 in coding exon 7 and extending 23 nucleotides into intron 7 of the BRCA2 gene. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested; however a significant portion of the transcript is in-frame (Ambry internal data). This in-frame transcript, referred to as Δ(E6Q39_E8) in the literature, has been shown to perform complementation in mouse embryonic stem cells and maintains 90% activity in a homology-directed repair functional assay (Mesman, RLS et al. Genet Med 2020 08;22(8):1355-1365). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at