16-23635578-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024675.4(PALB2):c.968C>A(p.Ala323Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250708Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135604
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
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This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. -
This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 323 of the PALB2 protein (p.Ala323Glu). This variant is present in population databases (rs730881882, gnomAD 0.003%). 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: 182760). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative 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. -
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1
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not provided Uncertain:1
This variant is denoted PALB2 c.968C>A at the cDNA level, p.Ala323Glu (A323E) at the protein level, and results in the change of an Alanine to a Glutamic Acid (GCA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Ala323Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ala323Glu occurs at a position that is well conserved through mammals and is located in the DNA-binding region (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PALB2 Ala323Glu is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The c.968C>A (p.A323E) alteration is located in exon 4 (coding exon 4) of the PALB2 gene. This alteration results from a C to A substitution at nucleotide position 968, causing the alanine (A) at amino acid position 323 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at