chr16-23626235-C-T
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>A variant causes a splice donor, 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 Likely pathogenic (★★).
Frequency
Consequence
NM_024675.4 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:3
The c.2748+1G>A variant is located in the canonical splice site of intronic region, following exon 7 of the PALB2 gene. This null variant causes loss-of-function through known disease mechanisms and is not found in the gnomAD genomes/exomes Database. Additionally, this alteration was identified in a 62-year-old Korean female diagnosed with triple-negative breast cancer. The patient has a family history of pancreatic cancer, gastric cancer, and liver cancer within first-degree relatives. Based on the available evidence, this variant is classified as pathogenic. -
The c.2748+1G>A intronic variant results from a G to A 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been identified in multiple individuals diagnosed with breast cancer (Zhang K et al. Breast Cancer Res Treat, 2017 Dec;166:865-873; Deng M et al. Int J Cancer, 2019 Sep;145:1517-1528; Petridis C et al. Cancer Epidemiol Biomarkers Prev, 2019 Jul;28:1162-1168; Zhou J et al. Cancer, 2020 Jul;126:3202-3208). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 to A 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. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in 3 individuals affected with breast cancer and 1 individual affected with breast or ovarian cancer (PMID: 30720863, 31263054, 33471991, 34113003). This variant has not been identified 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. -
Familial cancer of breast Pathogenic:3
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. -
- -
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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 28825143, 31263054). ClinVar contains an entry for this variant (Variation ID: 484205). 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. -
Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1
- -
not provided Pathogenic:1
This variant is located in a canonical splice-donor site and interferes with normal PALB2 mRNA splicing. The variant has been reported in an individual with breast cancer in the published literature (PMID: 28825143 (2017)). Based on the available information, this variant is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at