rs587776426
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_024675.4(PALB2):c.3456dupA(p.Pro1153fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PALB2
NM_024675.4 frameshift
NM_024675.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.52
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 Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-23603563-G-GT is Pathogenic according to our data. Variant chr16-23603563-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 128142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.3456dupA | p.Pro1153fs | frameshift_variant | 13/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.3456dupA | p.Pro1153fs | frameshift_variant | 13/13 | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727236
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 13, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 11, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 08, 2023 | This sequence change creates a premature translational stop signal (p.Pro1153Thrfs*4) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the PALB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25099575, 25452441, 26681312). ClinVar contains an entry for this variant (Variation ID: 128142). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200671; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 03, 2017 | - - |
| Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2023 | Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Antoniou et al., 2014; Couch et al., 2015; Tung et al., 2015; Schoolmeester et al., 2017; Dudley et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26681312, 29922827, 25099575, 25452441, 28709830, 29360161, 25186627, 34326862) - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, no assertion criteria provided | literature only | SNPedia | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | PALB2: PVS1, PM2 - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 21, 2022 | This variant inserts 1 nucleotide in exon 13 of the PALB2 gene, creating a frameshift and premature translation stop signal in the last coding exon. The mutant protein is expected to escape nonsense-mediated decay and be expressed as a truncated protein with disrupted WD40 domain that is important for PALB2 function (PMID: 31757951, 33139182). This variant has been reported in individuals affected with breast cancer (PMID: 25099575, 25186627, 25452441, 26681312, 28709830). 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 Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 10, 2022 | The c.3456dupA pathogenic mutation, located in coding exon 13 of the PALB2 gene, results from a duplication of A at nucleotide position 3456, causing a translational frameshift with a predicted alternate stop codon (p.P1153Tfs*4). This pathogenic mutation has been identified in multiple individuals with a personal history of breast cancer and a family history of breast and/or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11; Tung N et al. Cancer 2015 Jan;121(1):25-33; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Schoolmeester JK et al. Hum. Pathol. 2017 Jul;70:14-26; Dudley B et al. Cancer. 2018 Apr;124(8):1691-1700). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 12, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Aug 29, 2023 | The PALB2 c.3456dup (p.Pro1153fs) variant has been reported in the medical literature in individuals with breast cancer (Antoniou A et al., PMID: 25099575; Couch F et al., PMID: 25452441; Susswein L et al., PMID: 26681312). This variant causes a frameshift by insertion of one nucleotide leading to premature termination. This frameshift occurs in the last exon and is not predicted to lead to nonsense mediated decay, although it disrupts the last 34 amino acids of PALB2, which are suggested to be necessary for protein function (Quinodoz M et al., PMID: 35120630). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been submitted to ClinVar as pathogenic by 11 laboratories (variation ID: 128142). Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. - |
PALB2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 01, 2023 | The PALB2 c.3456dupA variant is predicted to result in a frameshift and premature protein termination (p.Pro1153Thrfs*4). This variant has been reported in individuals with breast cancer and individuals with pancreatic cancer (Table S2, Antoniou et al. 2014. PubMed ID: 25099575; Table 1, Schoolmeester et al. 2017. PubMed ID: 28709830; Table 2, Dudley et al. 2018. PubMed ID: 29360161; eTable 3, Hu et al. 2018. PubMed ID: 29922827; Supplement, Tung et al. 2014. PubMed ID: 25186627; Table S1, Couch et al. 2014. PubMed ID: 25452441; Table A4, Abe et al. 2019. PubMed ID: 30883245). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128142/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at