rs587776527
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_024675.4(PALB2):c.3256C>T(p.Arg1086Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
PALB2
NM_024675.4 stop_gained
NM_024675.4 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.64
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 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
PP5
Variant 16-23607958-G-A is Pathogenic according to our data. Variant chr16-23607958-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23607958-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.3256C>T | p.Arg1086Ter | stop_gained | 12/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.3256C>T | p.Arg1086Ter | stop_gained | 12/13 | 1 | NM_024675.4 | ENSP00000261584 | P1 | |
| ENST00000561764.1 | n.185+575G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251482Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727200
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial cancer of breast Pathogenic:6
| Likely pathogenic, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
| 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.Arg1086*) 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 (rs587776527, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with pancreatic cancer (PMID: 19264984, 23561644, 25356972, 26283626, 26315354, 26845104). ClinVar contains an entry for this variant (Variation ID: 126729). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | research | deCODE genetics, Amgen | Jul 21, 2023 | The variant NM_024675.4:c.3256C>T (chr16:23607958) in PALB2 was detected in 33 heterozygotes out of 58K WGS Icelanders (MAF= 0,028%). Following imputation in a set of 166K Icelanders (71 imputed heterozygotes) we observed an association with breast cancer using 6908 cases and 292623 controls (OR= 5.57, P= 6.93e-05). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 14, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 14, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 27, 2023 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 02, 2023 | This nonsense variant causes the premature termination of PALB2 protein synthesis. The frequency of this variant in the general population, 0.000035 (4/113760 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 26845104 (2016), 28779002 (2017), 29752822 (2018), 30720863 (2019), 31841383 (2020)), ovarian cancer (PMID: 26315354 (2015), 26720728 (2016)), prostate cancer (PMID: 32853339 (2021)), and pancreatic cancer (PMID: 23561644 (2013). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2024 | Nonsense 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 19264984, 23561644, 26720728, 26315354, 28825143); 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: 26283626, 26845104, 23935836, 28779002, 29922827, 19264984, 23561644, 25525159, 25356972, 21165770, 26315354, 24870022, 26720728, 26546047, 26681312, 28495237, 28736627, 20888394, 28825143, 29752822, 28724667, 30720863, 31263054, 31768816, 28418444, 31921681, 32068069, 32339256, 34426522, 32546565, 32566746, 30982232, 33169439, 32853339, 31619740, 34113003, 34917121, 33471991, 36278678, 35534704, 36243179, 36988593, 34949788, 36623239, 34439348) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| 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 | Color Diagnostics, LLC DBA Color Health | Nov 07, 2022 | This variant changes 1 nucleotide in exon 12 of the PALB2 gene, creating a 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: 26283626, 28724667, 29752822, 32566746), ovarian cancer (PMID 26720728) and pancreatic cancer (PMID: 19264984, 23561644, 25356972). This variant also has been detected in a breast cancer case-control meta-analysis in 7/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010200). This variant has been identified in 5/251482 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 | Apr 08, 2022 | The p.R1086* pathogenic mutation (also known as c.3256C>T), located in coding exon 12 of the PALB2 gene, results from a C to T substitution at nucleotide position 3256. This changes the amino acid from an arginine to a stop codon within coding exon 12. This mutation has been reported in multiple unrelated families with breast, ovarian and pancreatic cancer histories (Jones S et al. Science. 2009 Apr;324:217; Grant RC et al. Hum. Genomics. 2013 Apr;7:11; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Norquist BM et al. JAMA Oncol. 2016 Apr;2:482-90; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). Another large case-control study identified this alteration in 1/1996 breast cancer cases and 1/1998 non-cancer controls, with the one case having bilateral breast cancer at 44 years of age (Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Li JY et al. Int. J. Cancer. 2019 Jan;144(2):281-289). 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. - |
Pancreatic cancer, susceptibility to, 3 Pathogenic:1Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Apr 10, 2009 | - - |
| Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
PALB2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 25, 2018 | The PALB2 c.3256C>T (p.Arg1086Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, it has been reported in a heterozygous state in at least eleven individuals with cancer, including five with pancreatic cancer, three with breast cancer (one bilateral), and one with ovarian cancer (Jones et al. 2009; Grant et al. 2013; Thompson et al. 2015; Zhen et al. 2015; Norquist et al. 2016; Susswein et al. 2016; Sun et al. 2017). Five of these individuals had a family history of cancer. Although the p.Arg1086Ter variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of condition penetrance and prevalence estimates. Control data are unavailable for this variant, which is reported at a frequency of 0.000036 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the available evidence, the p.Arg1086Ter variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
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 | Mar 27, 2022 | - - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 12, 2022 | - - |
Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | This sequence change creates a premature translational stop signal (p.Arg1086*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD (no frequency). This variant has been reported in individual(s) affected with pancreatic cancer (PMID: 19264984, 23561644, 25356972), breast cancer (PMID: 26283626, 26845104), and ovarian cancer (PMID: 26315354). ClinVar classifies this variant as Pathogenic, rated 2 stars, with 10 submissions, 10 publications (19264984, 23561644, 25356972, 26283626, 26315354 and 5 more) and no conflicts. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). Therefore, this variant has been classified as pathogenic. - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2022 | Variant summary: PALB2 c.3256C>T (p.Arg1086X) 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 allele was found at a frequency of 2e-05 in 251482 control chromosomes (gnomAD). c.3256C>T has been reported in the literature in multiple individuals affected with various cancers, including breast/ovarian/pancreas/prostate/colon (e.g. Jones_2009, Grant_2013, Zhen_2015, Decker_2017, Yang_2020, Dorling_2021). The variant was reported in several affected individuals in a family (Grant_2013). Overall, these data indicate that the variant is very likely to be associated with disease. Funcational studies using a cell culture based homologous recombination assay demonstrated that the variant had complete loss of function, with similar activity seen in the empty vector control (Zhang_2021). Eleven ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and nine as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A
Vest4
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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