rs876658196
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BP4
The NM_024675.4(PALB2):c.3392T>C(p.Ile1131Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. I1131V) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.3392T>C | p.Ile1131Thr | missense_variant | 13/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3392T>C | p.Ile1131Thr | missense_variant | 13/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727240
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 30, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 04, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 07, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the WD40-like repeats of the PALB2 protein, which are required for interactions with the BRCA2, POLH, and RAD51C proteins (PMID: 24141787, 24485656). While functional studies have not been performed to directly test the effect of this variant on PALB2 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant disrupts the WD40-like repeats of the PALB2 protein, which are required for interactions with the BRCA2, POLH, and RAD51C proteins (PMID: 24141787, 24485656). While functional studies have not been performed to directly test the effect of this variant on PALB2 protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 229790). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1131 of the PALB2 protein (p.Ile1131Thr). - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 07, 2023 | This missense variant replaces isoleucine with threonine at codon 1131 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 PALB2-related disorders 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 | Aug 03, 2022 | The p.I1131T variant (also known as c.3392T>C), located in coding exon 13 of the PALB2 gene, results from a T to C substitution at nucleotide position 3392. The isoleucine at codon 1131 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 12, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 16, 2016 | Variant summary: The PALB2 c.3392T>C (p.Ile1131Thr) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome. This variant is absent in approximately 121182 control chromosomes from the large and broad populations of ExAC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant has currently been classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at