chr16-23635083-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_024675.4(PALB2):c.1463G>C(p.Ser488Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. S488G) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.1463G>C | p.Ser488Thr | missense_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.1463G>C | p.Ser488Thr | missense_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 14, 2022 | This missense variant replaces serine with threonine at codon 488 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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 | Mar 02, 2021 | The p.S488T variant (also known as c.1463G>C), located in coding exon 4 of the PALB2 gene, results from a G to C substitution at nucleotide position 1463. The serine at codon 488 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well 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. - |
Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | The PALB2 c.1463G>T (p.Ser488Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. Both Polyphen and SIFT in silico tools predicted a benign outcome for this variant. The frequency of this variant in the general population is listed in the gnomAD as 0.00001414. There are 5 entries for this mutation in ClinVar all described it as a variant of uncertain significance. The current evidence for this variant puts it in the uncertain significance category. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2017 | This variant is denoted PALB2 c.1463G>C at the cDNA level, p.Ser488Thr (S488T) at the protein level, and results in the change of a Serine to a Threonine (AGC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Ser488Thr was not observed in large population cohorts (Lek 2016). Since Serine and Threonine share similar properties, this is considered a conservative amino acid substitution. PALB2 Ser488Thr is not located in known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PALB2 Ser488Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 488 of the PALB2 protein (p.Ser488Thr). This variant is not present in population databases (gnomAD no frequency). 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: 420536). 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 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at