rs183489969
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_024675.4(PALB2):c.3054G>T(p.Glu1018Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1018A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PALB2
NM_024675.4 missense
NM_024675.4 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: -0.240
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3765996).
BP6
Variant 16-23621421-C-A is Benign according to our data. Variant chr16-23621421-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420826.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461830Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727216
GnomAD4 exome
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3
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1461830
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30
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1
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727216
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2023 | The p.E1018D variant (also known as c.3054G>T), located in coding exon 10 of the PALB2 gene, results from a G to T substitution at nucleotide position 3054. The glutamic acid at codon 1018 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been identified in an individual with a personal diagnosis of pancreatic cancer as well as family history of pancreatic cancer (Zhen DB et al. Genet. Med., 2015 Jul;17:569-77). This alteration demonstrated normal function in a functional study including a homology-directed DNA repair (HDR) assay, a PARP inhibitor sensitivity assay, and a cisplatin sensitivity assay (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 19, 2021 | This missense variant replaces glutamic acid with aspartic acid at codon 1018 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant has functional DNA repair activity in vitro (PMID: 31757951). To our knowledge, this variant has been reported in individuals affected with pancreatic cancer in the literature (PMID: 25356972). A similar variant that produces the same protein change c.3054G>C (p.Glu1018Asp) is not associated with breast or pancreatic cancer (PMID: 30287823, 32980694). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD) although the c.3054G>C (p.Glu1018Asp) variant is reported in gnomAD. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Pancreatic cancer, susceptibility to, 3 Uncertain:1
| Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2016 | This variant is denoted PALB2 c.3054G>T at the cDNA level, p.Glu1018Asp (E1018D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAT). This variant has been observed in at least one individual with a personal and family history of pancreatic cancer (Zhen 2014). PALB2 Glu1018Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. PALB2 Glu1018Asp occurs at a position that is conserved in mammals and is located in the WD4 repeat region, as well as the regions required for POLH DNA synthesis stimulation and interaction with BRCA2, POLH, RAD51 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Glu1018Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Familial cancer of breast Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 05, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;D
REVEL
Benign
Sift
Benign
D;D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MutPred
0.31
.;Gain of relative solvent accessibility (P = 0.0479);
MVP
0.55
MPC
0.30
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at