rs753153576
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_024675.4(PALB2):c.2748+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★).
Frequency
Consequence
NM_024675.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251470Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135916
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727234
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:4
PM2_SUP, PVS1_STR -
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Canonical splice site variant demonstrated to result in an in-frame loss of exon 7 (Lopez-Perolio 2019), which includes a critical region (Oliver 2009, Buisson 2010, Buisson 2014, UniProt); Observed in individuals with a personal or family history including breast, ovarian, and other cancers (Yang 2020); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30003184, 30890586, 29922827, 31447099, 31841383, 31589614) -
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Familial cancer of breast Pathogenic:4
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The c.2748+1G>T variant in the PALB2 gene is predicted to disrupt a canonical splice donor site and thus alter mRNA splicing. This variant is extremely rare in the general population. This c.2748+1G>T variant in the PALB2 gene is classified as likely pathogenic. -
This sequence change affects a donor splice site in intron 7 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs753153576, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 28825143, 30720863, 31263054, 31841383). ClinVar contains an entry for this variant (Variation ID: 186035). Studies have shown that disruption of this splice site results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 30890586). This variant disrupts the WD40-like repeats of the PALB2 protein, which are required for interactions with the BRCA2, POLH, and RAD51C proteins (PMID: 24141787, 24485656). While functional studies have not been performed to directly test the effect of this variant on PALB2 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -
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:3
PVS1; PM2_SUP -
The c.2748+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 7 of the PALB2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay, though the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
This variant causes a G>T nucleotide substitution at the +1 position of intron 7 of the PALB2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at