rs864622498
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.93_94insA(p.Leu32ThrfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PALB2
NM_024675.4 frameshift
NM_024675.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.504
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 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 62 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-23638084-G-GT is Pathogenic according to our data. Variant chr16-23638084-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220371.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.93_94insA | p.Leu32ThrfsTer11 | frameshift_variant | 2/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.93_94insA | p.Leu32ThrfsTer11 | frameshift_variant | 2/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461708Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727158
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30
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727158
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GnomAD4 genome
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Likely pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Leu32Thrfs*11) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). 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: 25452441). ClinVar contains an entry for this variant (Variation ID: 220371). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 06, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 17, 2024 | This variant inserts 1 nucleotide in exon 2 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 25452441, 27878467, 28008555, 29785153, 37239058). 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 | GeneKor MSA | Jan 01, 2020 | This variant is a single base pair insertion in exon 2 of the PALB2 mRNA, causing a frameshift after codon 32 and this creates a premature translational stop signal 11 amino acid residues later. This is expected to result in an absent or disrupted protein product. Truncating variants in the PALB2 gene are known to be pathogenic (PMID: 17200668, 24136930, 25099575). This variant has been described in the international literature in an individual with breast cancer (PMID: 25452441) and in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID:220371). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 27, 2023 | The c.93dupA pathogenic mutation, located in coding exon 2 of the PALB2 gene, results from a duplication of A at nucleotide position 93, causing a translational frameshift with a predicted alternate stop codon (p.L32Tfs*11). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation has been detected in multiple individuals with a personal and/or family history of breast cancer (Couch FJ et al. J. Clin. Oncol., 2015 Feb;33:304-11; Pritzlaff M et al. Breast Cancer Res. Treat., 2017 02;161:575-586; Yadav S et al. Fam. Cancer, 2017 07;16:319-328; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This mutation has also been reported in a male patient with biliary cancer (Schrader KA et al. JAMA Oncol, 2016 Jan;2:104-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); 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: 25452441, 26556299, 27878467, 29785153, 28008555, 31159747, 31937788) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Pancreatic cancer, susceptibility to, 3 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 24, 2021 | - - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 18, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 31, 2024 | This sequence change creates a premature translational stop signal (p.Leu32Thrfs*11) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-offunction variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). 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: 25452441). ClinVar contains an entry for this variant (Variation ID: 220371). For these reasons, this variant has been classified 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