rs515726104
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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):βc.3048delβ(p.Phe1016LeufsTer17) 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 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
PALB2
NM_024675.4 frameshift
NM_024675.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.77
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-23621426-CA-C is Pathogenic according to our data. Variant chr16-23621426-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23621426-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.3048del | p.Phe1016LeufsTer17 | frameshift_variant | 10/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.3048del | p.Phe1016LeufsTer17 | frameshift_variant | 10/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 | |
| ENST00000561764.1 | n.420-2470del | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461822Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727216
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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:14
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 | Division of Medical Genetics, University of Washington | Jun 17, 2019 | This variant leads to a translational frameshift and the introduction of a premature termination codon 17 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of PALB2 is a well-established mechanism of disease for increased breast cancer risk (Rahman 2007, Janatova 2013, Antoniou 2014). This variant has an allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with breast cancer (Zheng 2012, Churpek 2015, Tung 2015). Thus, this variant is interpreted as pathogenic. - |
| Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Phe1016Leufs*17) 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 present in population databases (rs515726104, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21932393, 25428789). ClinVar contains an entry for this variant (Variation ID: 126707). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 11, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 24, 2024 | - - |
| 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. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 13, 2023 | The PALB2 c.3048del (p.Phe1016Leufs*17) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32339256 (2020), 30128536 (2019), 30287823 (2018), 29486991 (2018), 28888541 (2017), 27153395 (2016), 25428789 (2015), 25186627 (2015), 21932393 (2012), 22692731 (2012)), head and neck squamous cell carcinoma (PMIDs: 29625052 (2018), 26689913 (2015)), as well as in healthy individuals (PMID: 29922827 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 15, 2019 | DNA sequence analysis demonstrated the presence of a heterozygous 1 base-pair deletion in the PALB2 gene, c.3048del. This sequence change results in an amino acid frameshift and creates a premature stop codon 16 amino acids downstream of the mutation, p.Phe1016Leufs*17. This deletion is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PALB2 protein with potentially abnormal function. This sequence change has not been described in population databases (gnomAD, ExAC). The c.3048del sequence change has been identified in an African American woman with breast cancer, and a family history of colorectal cancer, leukemia, and pancreatic cancer (PMID: 21932393). This sequence change is likely causative of susceptibility to breast cancer and pancreatic cancer, however functional studies have not been performed to prove this conclusively. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 21932393, 25186627, 37169825); This variant is associated with the following publications: (PMID: 28888541, 21932393, 25186627, 25428789, 24870022, 22692731, 29625052, 26689913, 32339256, 30287823, 30128536, 29486991, 36451132, 27153395, 37169825, 29922827) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2021 | This variant deletes 1 nucleotide in exon 10 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21932393, 25428789, 27153395, 30128536, 30287823). In a breast cancer case-control study, this variant was identified in 1/7051 female breast cancer cases and was absent in any controls (PMID: 30287823). This variant has been identified in 1/246228 chromosomes 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 12, 2022 | The c.3048delT pathogenic mutation, located in coding exon 10 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 3048, causing a translational frameshift with a predicted alternate stop codon (p.F1016Lfs*17). This alteration has been reported in an African American woman diagnosed with invasive breast cancer at age 60 who also had a family history of pancreatic cancer (Zheng Y et al. Cancer 2012;118:1362-70). This variant was also reported in an African American woman with triple negative breast cancer diagnosed over the age of 45 (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149:31-9). 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. - |
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 | Nov 01, 2021 | - - |
PALB2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 11, 2024 | The PALB2 c.3048delT variant is predicted to result in a frameshift and premature protein termination (p.Phe1016Leufs*17). This variant has been reported many times in individuals with breast cancer (see for examples Zheng et al. 2012. PubMed ID: 21932393; Churpek et al. 2015. PubMed ID: 25428789). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PALB2 are expected to be pathogenic and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/126707). This variant is interpreted as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 09, 2019 | Variant summary: PALB2 c.3048delT (p.Phe1016LeufsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251448 control chromosomes (gnomAD). c.3048delT has been reported in the literature in individuals affected with breast and/or ovarian cancer (Zheng_2012, Tung_2014, Barrington_2018, Lu_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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SpliceAI score (max)
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