rs45447991
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_024675.4(PALB2):c.844A>G(p.Arg282Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R282S) has been classified as Likely benign.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.844A>G | p.Arg282Gly | missense_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.844A>G | p.Arg282Gly | missense_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251410Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135882
GnomAD4 exome AF: 0.0000588 AC: 86AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42AN XY: 727214
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer (Ramus et al., 2015; Decker et al., 2017; Dorling et al., 2021; Rahman et al., 2007); This variant is associated with the following publications: (PMID: 28779002, 26315354, 30287823, 19369211, 33471991, 36243179, 17200668) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 12, 2018 | - - |
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | Oct 10, 2018 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 22, 2020 | This missense variant replaces arginine with glycine at codon 282 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 ovarian cancer in the literature. This variant has been identified in 2/251410 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 | curation | Sema4, Sema4 | Aug 17, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 21, 2023 | The p.R282G variant (also known as c.844A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 844. The arginine at codon 282 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in multiple studies in breast and/or ovarian patients as well as unaffected control subjects (Rahman N et al. Nat. Genet., 2007 Feb;39:165-7; Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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. - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 27, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 282 of the PALB2 protein (p.Arg282Gly). This variant is present in population databases (rs45447991, gnomAD 0.003%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 231184). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 28, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at