Submissions for variant NM_000546.6(TP53):c.107C>A (p.Pro36Gln)

dbSNP: rs587781866

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000469733	SCV001481788	benign	Li-Fraumeni syndrome	2024-09-06	reviewed by expert panel	curation	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)
Ambry Genetics	RCV000130183	SCV000185020	likely benign	Hereditary cancer-predisposing syndrome	2019-03-19	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000213046	SCV000211734	uncertain significance	not provided	2014-06-27	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469733	SCV000545275	uncertain significance	Li-Fraumeni syndrome	2023-11-17	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000662689	SCV000785414	uncertain significance	Li-Fraumeni syndrome 1	2017-07-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130183	SCV000908804	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-10	criteria provided, single submitter	clinical testing	This missense variant replaces proline with glutamine at codon 36 of the TP53 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Yeast transactivation assays reported the variant protein to be functional (PMID 12826609 and the International Agency for Research on Cancer). 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.
Myriad Genetics, Inc.	RCV000662689	SCV004017879	uncertain significance	Li-Fraumeni syndrome 1	2023-04-11	criteria provided, single submitter	clinical testing	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.