rs764669864
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_024675.4(PALB2):c.3025C>T(p.Pro1009Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,812 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1009L) has been classified as Uncertain significance.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.3025C>T | p.Pro1009Ser | missense_variant | 10/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3025C>T | p.Pro1009Ser | missense_variant | 10/13 | 1 | NM_024675.4 | P1 | |
ENST00000561764.1 | n.420-2450G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152060Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251446Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461752Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12AN XY: 727178
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152060Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74280
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 16, 2020 | This missense variant replaces proline with serine at codon 1009 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with pancreatic cancer (PMID: 25356972). This variant has also been identified in 1/251446 chromosomes in the general population by the Genome Aggregation Database (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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 17, 2022 | The p.P1009S variant (also known as c.3025C>T), located in coding exon 10 of the PALB2 gene, results from a C to T substitution at nucleotide position 3025. The proline at codon 1009 is replaced by serine, an amino acid with similar properties. This variant was identified in 1/727 probands with pancreatic adenocarcinoma as well as a family history of pancreatic and/or other types of cancer (Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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. - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 11, 2022 | - - |
PALB2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 09, 2023 | The PALB2 c.3025C>T variant is predicted to result in the amino acid substitution p.Pro1009Ser. This variant has been reported in an individual with pancreatic cancer (Table 2, Zhen et al. 2015. PubMed ID: 25356972; Table S2, Chaffee et al. 2018. PubMed ID: 28726808). This variant is reported in 1 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-23632771-G-A). It is interpreted as uncertain significance in Clinvar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/409395/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 11, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal and family history of pancreatic cancer in published literature (Zhen 2015); This variant is associated with the following publications: (PMID: 24141787, 24485656, 19609323, 20871615, 25356972) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1009 of the PALB2 protein (p.Pro1009Ser). This variant is present in population databases (rs764669864, gnomAD 0.0009%). This missense change has been observed in individual(s) with a personal and/or family history of pancreatic cancer (PMID: 25356972). ClinVar contains an entry for this variant (Variation ID: 419928). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at