Total submissions: 21
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genesis Genomics | RCV000576336 | SCV007580119 | likely pathogenic | Li-Fraumeni syndrome 1 | criteria provided, single submitter | clinical testing | ||
| Institute for Genomic Medicine |
RCV006253857 | SCV007105572 | tier i - strong | Diffuse midline glioma, H3 K27M-mutant | 2024-10-25 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639). |
| Department of Pathology and Laboratory Medicine, |
RCV005365056 | SCV005918323 | likely pathogenic | Li-Fraumeni syndrome 1; Familial pancreatic carcinoma | 2020-07-22 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000457119 | SCV005425741 | likely pathogenic | Li-Fraumeni syndrome | 2023-10-02 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with methionine at codon 125 DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. One RNA study showed use of a cryptic donor splice site and exon 4 skipping (PMID: 34675114). Functional studies have shown the mutant protein to be defective in transactivation activity (PMID: 10761705, 12826609, 28369373) and functional in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals affected with adrenocortical carcinoma (PMID: 26014290, 28369373; DOI:10.7759/cureus.24602) and individuals affected with early-onset breast cancer (PMID: 25503501, 34675114). This variant has been reported in additional individuals affected with breast cancer (PMID: 26845104, 31206626, 30128536, 34675114), ovarian cancer (PMID: 30216591), and bladder urothelial carcinoma (PMID: 34240179). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position, p.Thr125Arg and p.Thr125Lys, are known to be disease-causing (ClinVar variation ID: 376667, 216465), indicating that threonine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Molecular Diagnostics Laboratory, |
RCV000162461 | SCV005407754 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-07-20 | criteria provided, single submitter | clinical testing | c.374C>T, located in exon 4 of the TP53 gene, is predicted to result in the substitution of Threonine by Methionine at codon 125, p.(Thr125Met). This variant is found in 1/31400 alleles at a frequency of 0.003% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.5) (PP3_moderate). Functional studies show conflicting results. Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is no evidence of a dominant negative effect and no loss of function according to Giacomelli 2018 (PMID: 30224644). At least, this variant has been reported in 10 Chompret individuals, which awards 5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 26014290, 32457520) (PS4). It has been reported in ClinVar (1x as pathogenic, 26x as likely pathogenic, 1x as uncertain significance), LOVD (1x as likely pathogenic) and CancerHotspots (16 somatic observations, PM1). Based on the currently available information, c.374C>T is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000457119 | SCV005395171 | likely pathogenic | Li-Fraumeni syndrome | 2024-09-09 | criteria provided, single submitter | clinical testing | Variant summary: TP53 c.374C>T (p.Thr125Met) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. One predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. This variant is not found in the 1612278 control chromosomes (gnomAD). c.374C>T has been reported in the literature in heterozygous individuals affected with Li-Fraumeni Syndrome, ovariant cancer or breast cancer (Maxwell_2015, Shirts_2016, Zerdoumi_2017, Weber-Lassalle_2018, Kansuttiviwat_2024). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed a dominant negative effect (Zerdoumi_2017). The most pronounced variant effect results in 68% reduction in TP53 transcriptional activity in lymphocytes. The following publications have been ascertained in the context of this evaluation (PMID: 26014290, 38355628, 25503501, 26845104, 30216591, 28369373). ClinVar contains an entry for this variant (Variation ID: 183748). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Clinical Genetics Laboratory, |
RCV000237013 | SCV005198845 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
| Center for Genomic Medicine, |
RCV004668821 | SCV005094462 | likely oncogenic | Neoplasm | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003462117 | SCV004206216 | pathogenic | Adrenocortical carcinoma, hereditary | 2023-10-19 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000237013 | SCV003917884 | likely pathogenic | not provided | 2023-07-01 | criteria provided, single submitter | clinical testing | TP53: PM2, PM5, PS4:Moderate |
| Cancer Variant Interpretation Group UK, |
RCV000162461 | SCV002760194 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-14 | criteria provided, single submitter | curation | Data included in classification: aGVGD: Class C65 and BayesDel score 0.5 (PP3_mod) 16 entries on cancer hotspots (PM1_mod) Bougeard et al. 2015: ACC in 2 children, Rana et al, 2019: 4 breast cancer cases and 1 sarcoma case, 14 observations in Ambry lab, 6 of which meet Chompret criteria (PS4_str) Data not included in classification: Conflicting functional evidence: Giacomelli et al. Nat Genet. 2018: NO DNE AND NO LOF Kato et al. PNAS 2003: Transactivation Class: non-functional Zerdoumi et al. HMG 2017: Dominant negative effect: ~75% decrease in p53 functionality score of lymphocytes compared to wild-type. Other classifications: Invitae (2020): Pathogenic; Ambry (2020) Counsyl (2016), Color (2015): Likely pathogenic; GeneDx (2019): VUS |
| Sema4, |
RCV000162461 | SCV002530451 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-27 | criteria provided, single submitter | curation | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000237013 | SCV001134868 | likely pathogenic | not provided | 2019-02-12 | criteria provided, single submitter | clinical testing | The best available variant frequency is uninformative. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function. |
| Color Diagnostics, |
RCV000162461 | SCV000691590 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2025-06-30 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with methionine at codon 125 DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. One RNA study has shown that this variant results in activation of a cryptic donor splice site and exon 4 skipping (PMID: 34675114). Functional studies have shown the mutant protein to be defective in transactivation activity (PMID: 10761705, 12826609, 28369373) but functional in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals meeting the Chompret criteria for Li-Fraumeni syndrome, including individuals affected with adrenocortical carcinoma (PMID: 26014290, 2836937335664418, 39810221) and individuals affected with early-onset breast cancer (PMID: 25503501, 34675114). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position, p.Thr125Arg and p.Thr125Lys, are known to be disease-causing (ClinVar variation ID: 376667, 216465), indicating that threonine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Labcorp Genetics |
RCV000457119 | SCV000545359 | pathogenic | Li-Fraumeni syndrome | 2025-11-02 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 125 of the TP53 protein (p.Thr125Met). This variant is present in population databases (rs786201057, gnomAD 0.01%). This missense change has been observed in individuals with adrenocortical carcinoma, breast cancer, and/or Li-Fraumeni-associated cancers (PMID: 25503501, 26014290, 26845104; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183748). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). This variant disrupts the p.Thr125 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 16508005; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000237013 | SCV000292695 | uncertain significance | not provided | 2025-06-20 | criteria provided, single submitter | clinical testing | Although this variant has been observed in individuals with a personal history of LFS-related cancers, such as adrenocortical carcinoma or early-onset breast cancer, it has not to our knowledge been reported in a family meeting classic LFS criteria or as a de novo variant, and it has also been reported in unaffected adults and others whose histories are not consistent with LFS (PMID: 26014290, 25503501, 26845104, 28861920, 29922827, 30216591, 30128536, 31206626, 34675114, 38355628, 39810221); Published functional studies demonstrate significantly reduced transactivation in some studies but higher activity in others, and no loss of growth suppression activity (PMID: 12826609, 27022024, 30224644, 29979965, 34675114); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies investigating splicing found a low level of aberrant transcripts also present in wildtype controls, suggesting they may be naturally occurring isoforms (PMID: 34675114); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27237367, 19046423, 21118481, 26849095, 26845104, 14559903, 20436704, 25503501, 10761705, 27998968, 27022024, 28369373, 26014290, 29319699, 12826609, 29079180, 30216591, 28861920, 30352134, 29922827, 30128536, 28472496, 30720243, 30840781, 31016814, 31206626, 31105275, 29979965, 30224644, 34675114, 34273903, 36243179, 31794323, 35664418, 35426462, 15510160, 37057674, 39810221, 38355628) |
| University of Washington Department of Laboratory Medicine, |
RCV000162461 | SCV000266132 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-11-20 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000162461 | SCV000212818 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2025-11-21 | criteria provided, single submitter | clinical testing | The p.T125M variant (also known as c.374C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 374. The threonine at codon 125 is replaced by methionine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). However, studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been reported in multiple individuals with early-onset breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Weitzel JN et al. Cancer. 2019 Aug;125:2829-2836) as well as in two individuals with childhood-onset adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol. 2015 Jul;33:2345-52). Another alteration at the same codon, p.T125R (c.374C>G), has been reported in several families meeting clinical criteria for Li Fraumeni syndrome (Morgan J et al Hum Mutat. 2010 Apr;31(4):484-91; Waszak SM et al. Lancet Oncol. 2018 06;19:785-798; Li JY et al. Int J Cancer. 2019 01;144:281-289). In addition, several functional studies indicate that p.T125R is deleterious (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387; Menendez D et al. Mol. Cell. Biol. 2006 Mar;26:2297-308). The p.T125M amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Clinical Genetics and Genomics, |
RCV004797602 | SCV005419175 | likely pathogenic | TP53-related disorder | 2024-10-01 | no assertion criteria provided | clinical testing | |
| BRCAlab, |
RCV000162461 | SCV002589020 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-08-26 | no assertion criteria provided | clinical testing | |
| Counsyl | RCV000576336 | SCV000677813 | likely pathogenic | Li-Fraumeni syndrome 1 | 2016-10-18 | no assertion criteria provided | clinical testing | This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. |