17-7676262-G-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. BS3BS2BP4PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.107C>A variant in TP53 is a missense variant predicted to cause substitution of proline by glutamine at amino acid 36 (p.Pro36Gln). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: Invitae). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.07; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. Although SpliceAI predicts a weak potential splice effect, expert review suggests that there is no actual impact on the native site, and the variant is therefore considered to have no impact on splicing (BP4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -7; VCEP specifications version 2.0; 9/6/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000031/MONDO:0007903/009
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 58
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Uncertain:2
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. -
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Li-Fraumeni syndrome Uncertain:1Benign:1
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 36 of the TP53 protein (p.Pro36Gln). 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: 141597). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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. -
The NM_000546.6: c.107C>A variant in TP53 is a missense variant predicted to cause substitution of proline by glutamine at amino acid 36 (p.Pro36Gln). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: Invitae). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.07; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. Although SpliceAI predicts a weak potential splice effect, expert review suggests that there is no actual impact on the native site, and the variant is therefore considered to have no impact on splicing (BP4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -7; VCEP specifications version 2.0; 9/6/2024) -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This missense variant replaces proline with glutamine at codon 36 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown that this variant is functional in yeast transcriptional transactivation assays and human cell growht supression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-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. -
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. -
not specified Uncertain:1
Variant summary: TP53 c.107C>A (p.Pro36Gln) results in a non-conservative amino acid change located in the Transactivation domain 2 (IPR040926) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251268 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.107C>A in individuals affected with Li-Fraumeni Syndrome has been reported. At least two publications report experimental evidence demonstrating that the variant does not substantially affect TP53 function (example: Giacomelli_2018, Kato_2003). The following publications have been ascertained in the context of this evaluation (PMID: 30224644, 12826609). ClinVar contains an entry for this variant (Variation ID: 141597). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
This variant is denoted TP53 c.107C>A at the cDNA level, p.Pro36Gln (P36Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). TP53 Pro36Gln has been observed as a somatic mutation in hematopoietic malignancy and reported to demonstrate functional transactivation activity similar to wild type in a yeast assay (IARC TP53 Database, Shiraishi 2004). TP53 Pro36Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Pro36Gln occurs at a position that is variable across species and is located in the transcription activation domain and region of interaction with HRMT1L2 (UniProt). Multiple in silico models predict formation of a new, cryptic splice acceptor site of equivalent strength as the natural splice acceptor site. In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Pro36Gln is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at