rs876659643
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_024675.4(PALB2):c.29G>T(p.Ser10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,250 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S10R) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.29G>T | p.Ser10Ile | missense_variant | 1/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.29G>T | p.Ser10Ile | missense_variant | 1/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461250Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726898
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2022 | The p.S10I variant (also known as c.29G>T), located in coding exon 1 of the PALB2 gene, results from a G to T substitution at nucleotide position 29. The serine at codon 10 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is highly 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 | Feb 02, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2022 | Variant summary: PALB2 c.29G>T (p.Ser10Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248042 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.29G>T has been reported in the literature in individuals affected with pancreatic cancer without strong evidence for causality (e.g. Kuruturkcan_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 12, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 02, 2017 | - - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 232241). 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 serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 10 of the PALB2 protein (p.Ser10Ile). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at