rs148921082
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_024675.4(PALB2):āc.1212T>Gā(p.Phe404Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,758 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 (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
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.1212T>G | p.Phe404Leu | missense_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.1212T>G | p.Phe404Leu | missense_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250904Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135642
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461758Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727188
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2023 | The p.F404L variant (also known as c.1212T>G), located in coding exon 4 of the PALB2 gene, results from a T to G substitution at nucleotide position 1212. The phenylalanine at codon 404 is replaced by leucine, an amino acid with highly similar properties. A functional analysis assessing the impact of missense alterations in the PALB2 chromatin association motif (ChAM) demonstrated that this alteration does not appear to impair or hinder chromatin association (Bleuyard JY et al. Wellcome Open Res, 2017 Nov;2:110). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 05, 2018 | - - |
PALB2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 19, 2023 | The PALB2 c.1212T>G variant is predicted to result in the amino acid substitution p.Phe404Leu. To our knowledge, this variant has not been reported in the literature in individuals with PALB2-related disorders. A functional study of this variant showed no obvious defects on chromatin association (Bleuyard JY et al 2017. PubMed ID: 29387807). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23646655-A-C). In ClinVar, this variant is classified as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/410195/). 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 | Jul 13, 2020 | Published functional studies demonstrated no obvious defect in chromatin association (Bleuyard et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29387807) - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | 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. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 29387807, 33964450). 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. ClinVar contains an entry for this variant (Variation ID: 410195). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is present in population databases (rs148921082, gnomAD 0.003%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 404 of the PALB2 protein (p.Phe404Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at