17-7676154-G-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. BP4BS2_SupportingBS3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). ). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID:12826609, 30224644) Finally, this variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting, Invitae internal data). In summary, TP53 c.215C>A; p.Pro72His meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_supporting, BP4, BS3, BS2_supporting. PM2_Supporting should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000071/MONDO:0007903/009
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.215C>A | p.Pro72His | missense_variant | 4/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.215C>A | p.Pro72His | missense_variant | 4/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461570Hom.: 1 Cov.: 80 AF XY: 0.0000165 AC XY: 12AN XY: 727076
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 15, 2021 | This missense variant replaces proline with histidine at codon 72 of the TP53 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 | curation | Sema4, Sema4 | Mar 10, 2022 | - - |
Li-Fraumeni syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 72 of the TP53 protein (p.Pro72His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 185120). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 28, 2023 | This missense variant replaces proline with histidine at codon 72 of the TP53 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. - |
Li-Fraumeni syndrome 1 Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Apr 19, 2021 | This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). ). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644) Finally, this variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting, Invitae internal data). In summary, TP53 c.215C>A; p.Pro72His meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_supporting, BP4, BS3, BS2_supporting. PM2_Supporting should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at