rs774949203
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_024675.4(PALB2):c.109-12T>A variant causes a splice polypyrimidine tract, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
PALB2
NM_024675.4 splice_polypyrimidine_tract, intron
NM_024675.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 5.16
Genes affected
PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 16-23637964-A-T is Pathogenic according to our data. Variant chr16-23637964-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 490064.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=1}. Variant chr16-23637964-A-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.109-12T>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.109-12T>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251448Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
GnomAD3 exomes
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135902
Gnomad AFR exome
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GnomAD4 exome Cov.: 29
GnomAD4 exome
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29
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2020 | Non-canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Kraus 2017); Observed in individuals with personal and/or family history of breast cancer (Hellebrand 2011, Kraus 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27616075, 21618343) - |
Likely pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Dec 04, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Andreas Laner. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change falls in intron 2 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with a personal or family history of breast cancer (PMID: 21618343, 27616075). ClinVar contains an entry for this variant (Variation ID: 490064). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21618343; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 23, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 25, 2022 | This variant causes a T to A nucleotide substitution at the -12 position of intron 2 of the PALB2 gene. An RNA study has shown that this variant creates a cryptic splice acceptor site in intron 2, resulting in the retention of intronic sequence (c.108_109insTCTCCTCTAG) and a frameshift in the open reading frame (PMID: 27616075). This variant has been reported in at least five individuals affected with breast cancer (PMID: 21618343, 27616075; Communication with external laboratories and the German Breast Cancer Consortium). These individuals were presented with familial, early-onset, bilateral, or triple-negative breast cancer. This variant has been identified in 1/251448 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2023 | The c.109-12T>A intronic variant results from a T to A substitution 12 nucleotides upstream from coding exon 3 in the PALB2 gene. This alteration was detected in an individual diagnosed with breast cancer and RT-PCR showed an insertion of 10 base pairs resulting in a frameshift protein (Kraus C et al. Int J Cancer, 2017 Jan;140:95-102). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Fanconi anemia complementation group N Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 22, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -2
DS_AL_spliceai
Position offset: -12
Find out detailed SpliceAI scores and Pangolin per-transcript scores at