rs876659036
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.2968G>T(p.Glu990*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024675.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2968G>T | p.Glu990* | stop_gained | 9/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2968G>T | p.Glu990* | stop_gained | 9/13 | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251468Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Feb 05, 2021 | - - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2023 | This sequence change creates a premature translational stop signal (p.Glu990*) 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 (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 231227). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 06, 2020 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2022 | 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29752822, 30982232, 32068069, 32339256, 33193564, 34439348, 29922827, 29566657, 17200672, 33649982, 17200668, 25099575, 24136930, 17200671, 33811135, 32029870) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2024 | The p.E990* pathogenic mutation (also known as c.2968G>T), located in coding exon 9 of the PALB2 gene, results from a G to T substitution at nucleotide position 2968. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration has been identified in multiple Chinese breast and/or ovarian cancer patients (Kwong A et al. J Mol Diagn, 2020 04;22:544-554; Zhou J et al. Cancer, 2020 07;126:3202-3208; Hu ZY et al. Front Genet, 2020 Aug;11:829; Li JY et al. Int J Cancer, 2019 01;144:281-289; Wang J et al. Cancer Med, 2019 05;8:2074-2084). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 28, 2020 | This variant changes 1 nucleotide in exon 9 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 familial breast cancer (PMID: 32068069; Hu et al. 2020, doi.org/10.3389/fgene.2020.00829). This variant has been identified in 2/251468 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. - |
Breast neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Yang An-Suei Laboratory, Academia Sinica | - | - - |
Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PVS1+PS4_Moderate - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at