rs587776428
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_024675.4(PALB2):c.3507_3508del(p.His1170PhefsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., 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: 1.47
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 12 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-23603511-TGA-T is Pathogenic according to our data. Variant chr16-23603511-TGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23603511-TGA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.3507_3508del | p.His1170PhefsTer19 | frameshift_variant | 13/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3507_3508del | p.His1170PhefsTer19 | frameshift_variant | 13/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461866Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727230
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. Functional studies indicate this variant impacts protein function [PMID: 19423707, 19609323]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2023 | This sequence change results in a frameshift in the PALB2 gene (p.His1170Phefs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PALB2 protein and extend the protein by 1 additional amino acid residues. This variant is present in population databases (rs587781411, gnomAD 0.1%). This frameshift has been observed in individual(s) with breast, ovarian and prostate cancer and breast cancer (PMID: 24556621, 25099575, 25225577, 26283626, 26314354, 26786923). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3504_3505del. ClinVar contains an entry for this variant (Variation ID: 140978). This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Y1183*) have been determined to be pathogenic (PMID: 17200671). 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. - |
Likely pathogenic, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
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 | Baylor Genetics | Jul 06, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 28, 2023 | Criteria applied: PVS1_MOD,PS4,PM2_SUP_MOD,PP1 - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 21, 2022 | Frameshift variant predicted to result in an extension of the protein, as the last 17 amino acids are replaced with 18 different amino acids, which disrupts a portion of the seventh WD repeat and the critical region required for interaction with RAD51, BRCA2, POLH, and POLH DNA synthesis stimulation (Oliver 2009, Buisson 2010, Buisson 2014); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26283626, 28825143, 17200671, 26314360, 16793542, 19609323, 26315354, 24556621, 25225577, 25099575, 19423707, 19584259, 24998779, 29431189, 29752822, 32339256, 30982232, 28888541, 20871615, 24485656) - |
Pathogenic, no assertion criteria provided | literature only | SNPedia | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Fanconi anemia complementation group N Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 06, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 09, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2024 | The c.3507_3508delTC variant, located in coding exon 13 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 3507 to 3508, causing a translational frameshift with a predicted alternate stop codon (p.H1170Ffs*19). This alteration occurs at the 3' terminus of the PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, alters the last 17 amino acids of the protein and results in the elongation of the protein by one amino acid. However, these 3' amino acids are part of the functionally critical WD40 domain that is necessary for PALB2 function, stability, and interaction with BRCA2 (Oliver AW et al. EMBO Rep., 2009 Sep;10:990-6). This alteration has also been reported in multiple individuals with personal and/or family history suggestive of hereditary breast, ovarian, or prostate cancer (Leongamornlert D et al. Br J Cancer. 2014 Mar 18;110(6):1663-72; Hartley T et al. Hered Cancer Clin Pract. 2014 Aug 28;12(1):19; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371(6):497-506; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107(11); Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Zhang K et al. Breast Cancer Res. Treat. 2017 Dec;166:865-873; Lee JEA et al. J. Pathol. 2018 May;245:53-60; Li JY et al. Int. J. Cancer. 2019 01;144:281-289; Rowley SM et al. Genet. Med., 2019 04;21:913-922; Yadav S et al. J. Clin. Oncol., 2020 May;38:1409-1418). Further, Hartley et al., reported segregation of this alteration with disease in 4 out of 5 individuals from one family. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 07, 2020 | This variant deletes 2 nucleotides in the last coding exon 13 of the PALB2 gene, substituting the last 17 amino acids of the protein with 18 different amino acids. This variant may also be known as c.3504_3505del. The variant impacts the C-terminus of the WD40 repeats domain, a known functional domain (PMID: 16793542, 19423707). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals with personal and/or family history of breast and ovarian cancer (PMID: 25099575, 25225577, 26283626, 26315354, 26786923, 29752822, 29431189, 28825143) and prostate cancer (PMID: 24556621), including one family in which the variant segregates with three first-degree relatives with early-onset or bilateral breast cancer (PMID: 25225577). This variant has been identified in 1/31326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
PALB2-Related Disorders Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.3507_3508del ;p.(His1170Phefs*?) is a null frameshift variant (NMD) in the PALB2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 140978; 25225577; PMID: 26283626; PMID: 25099575; PMID: 24556621; PMID: 26786923)PS4. The variant is present at low allele frequencies population databases (rs587776428 – gnomAD 0.00006579%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 25225577, 24556621) - PP1_moderate. In summary, the currently available evidence indicates that the variant is likely pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at