rs180177092
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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.757_758del(p.Leu253IlefsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
PALB2
NM_024675.4 frameshift
NM_024675.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0860
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 16-23635787-TAG-T is Pathogenic according to our data. Variant chr16-23635787-TAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 126768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23635787-TAG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.757_758del | p.Leu253IlefsTer3 | frameshift_variant | 4/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.757_758del | p.Leu253IlefsTer3 | frameshift_variant | 4/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251366Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135880
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461850Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727234
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:26Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:9Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2018 | Variant summary: PALB2 c.757_758delCT (p.Leu253IlefsX3) 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 (eg. c.1240C>T/p.Arg414X, c.2167_2168delAT/p.Met723fsX21). The variant allele was found at a frequency of 8.2e-06 in 123596 control chromosomes. c.757_758delCT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer in heterozygous state and one individual with Fanconi anemia in compound heterozygous state (Walsh_2011, Casedei_2011, Tung_2015). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 12, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Leu253Ilefs*3) 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 (rs180177092, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer and breast cancer and/or ovarian cancer and Fanconi anemia (PMID: 17200671, 21285249, 22006311, 26845104, 26898890). ClinVar contains an entry for this variant (Variation ID: 126768). For these reasons, this variant has been classified as Pathogenic. - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Pathogenic and reported on 02-05-2020 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Oct 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 04, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 18, 2022 | PVS1, PM2, PS4_Strong - |
| 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 | Institute of Human Genetics, University of Leipzig Medical Center | Sep 13, 2024 | Criteria applied: PVS1,PM3,PM2_SUP,PM5_SUP - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2016 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 23, 2021 | This frameshift variant causes the premature termination of PALB2 protein synthesis. In addition, it has been reported in individuals with breast or endometrial cancer in the published literature (PMIDs: 26898890 (2016), 26681312 (2015) and 21285249 (2011)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2020 | 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 a significant frequency in large population cohorts (Lek 2016); Observed in several individuals with personal and/or family history of PALB2-related cancers (Jones 2009, Casadei 2011, Tung 2014, Caminsky 2016, Shirts 2016); This variant is associated with the following publications: (PMID: 23935381, 29753700, 26681312, 29706558, 19264984, 22006311, 21285249, 24240112, 25186627, 25099575, 21165770, 26898890, 26845104, 28152038, 17200671, 31159747) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | PALB2: PVS1, PM2 - |
| Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz. - |
Hereditary cancer-predisposing syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 23, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 17, 2022 | The c.757_758delCT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 757 to 758, causing a translational frameshift with a predicted alternate stop codon (p.L253Ifs*3). This mutation has been reported in both Fanconi anemia type-N (FA-N) and familial breast cancer cohorts (Reid S et al. Nat. Genet. 2007 Feb;39:162-4; Tischkowitz M et al. Proc. Natl. Acad. Sci. USA. 2007 Apr;104:6788-93; Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506; Tung N et al. Cancer. 2015 Jan;121:25-33; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Another study reported this mutation in a woman with peritoneal carcinoma and a family history significant for breast and/or ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7). It was also seen in a medulloblastoma cohort (Waszak SM et al. Lancet Oncol. 2018 06;19(6):785-798). In addition to the information 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This mutation is a 2 nucleotide deletion in exon 4 of the PALB2 gene. This result in a frameshift and the creation of a premature stop codon three amino acid residues later. This mutation has been described in international literature (https://grenada.lumc.nl; http://rgd.mcw.edu). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2022 | This variant deletes 2 nucleotides in exon 4 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 at least 10 individuals affected with breast, peritoneal and endometrial cancer and one unaffected individual (PMID: 21285249, 22006311, 23935381, 25186627, 26681312, 26845104, 33471991; Leiden Open Variation Database DB-ID PALB2_000005) and an individual affected with medulloblastoma (PMID: 29753700). This variant also has been reported in trans with another pathogenic PALB2 variant in an individual affected with biallelic Fanconi anemia (PMID: 17200671). This variant has been identified in 2/251366 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. - |
Fanconi anemia complementation group N Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 04, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 06, 2019 | - - |
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 | Dec 27, 2021 | - - |
PALB2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 24, 2024 | The PALB2 c.757_758delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu253Ilefs*3). This variant has been reported in the compound heterozygous state in a patient with Fanconi anemia who had Wilms tumor, AML, and medullobalstoma in addition to classic FA features (see patient GESH in Reid et al. 2007. PubMed ID: 17200671). This variant has also been reported in the heterozygous state in many patients with various other cancer types including gastric cancer (Fewings et al. 2018. PubMed ID: 29706558), breast cancer and / or endometrial cancer (Casadei et al. 2011. PubMed ID: 21285249; Susswein et al. 2016. PubMed ID: 26681312; Tung et al. 2015. PubMed ID: 25186627). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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/126768). Given the evidence, we too interpret c.757_758del (p.Leu253Ilefs*3) as pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 05, 2023 | _x000D_ Criteria applied: PVS1, PS4, PM2_SUP - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 09, 2023 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Aug 13, 2024 | According to the ClinGen ACMG PALB2 v1.1.0 criteria we chose these criteria: PVS1 (very strong pathogenic): PVS1 as per the PVS1 decision tree, PM3 (medium pathogenic): Reid et al., 2007, Nat Genet, comp het in Patient mit FA, erüllt 3 Kriterien (Wilms Tumor, hypoplastic thumb, microcephaly), => 2Punkte => mod, PM5 (supporting pathogenic): Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183* - |
Malignant tumor of breast;C1835817:Fanconi anemia complementation group N Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 05-28-2015 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
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Details are displayed if max score is > 0.2
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