rs35993958
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_000546.6(TP53):c.1079G>T(p.Gly360Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,746 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G360A) has been classified as Likely benign.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.1079G>T | p.Gly360Val | missense_variant | 10/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.1079G>T | p.Gly360Val | missense_variant | 10/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250440Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135450
GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461598Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 727066
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74330
ClinVar
Submissions by phenotype
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 15, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 21, 2023 | Variant summary: TP53 c.1079G>T (p.Gly360Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 1613746 control chromosomes. The observed variant frequency is above the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. c.1079G>T has been reported in the literature in individuals affected with neuroblastoma (Kudo_2018) without evidence for causality or segregation with diease. This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Co-occurrences with another pathogenic variant have been reported (ALK c.3824G>A, p.Arg1275Gln, Kudo_2018), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function suggesting it is functional (Said_2016, Kato_2003). The following publications have been ascertained in the context of this evaluation (PMID: 27297285, 12826609, 35352025, 30350464). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=7) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 20, 2015 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 13, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2021 | This variant is associated with the following publications: (PMID: 20597068, 30287823, 28945843, 25256751, 8577720, 25503501, 27297285, 30840781, 12826609, 31740566, 31320002, 14559903) - |
Li-Fraumeni syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at