chr16-23626399-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_024675.4(PALB2):c.2587-2A>C variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024675.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:1Uncertain:1
This sequence change affects an acceptor splice site in intron 6 of the PALB2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410189). Experimental studies have shown that sequence changes at this splice site disrupt the consensus splice site and strengthen a cryptic acceptor site in intron 6, located 42 nucleotides upstream of the natural splice site. This results in an alternative transcript with an in-frame insertion of 14 amino acids in the linker region between b-strand 7D (residues 855-860) and b-strand 1A (residues 868-877), but otherwise preserves the integrity of the reading frame (PMID: 30890586). Also, this alternative transcript has been shown to occur naturally in healthy individuals (PMID: 30890586). These studies suggest that the clinical significance of this splice variant may be uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.2587-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 7 in the PALB2 gene. This nucleotide position is highly conserved in available vertebrate species. The BDGP splice site prediction software does not produce a reliable prediction for the nearby native splice acceptor site. Using the ESEfinder splice site prediction tool, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at