NM_000546.6:c.375G>C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000546.6(TP53):c.375G>C(p.Thr125Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Pathogenic.
Frequency
Consequence
NM_000546.6 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:1
This sequence change affects codon 125 of the TP53 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TP53 protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 10864200, 21059199, 35974385; internal data). ClinVar contains an entry for this variant (Variation ID: 480746). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.375G nucleotide in the TP53 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 1467311, 9242456, 11420676, 18511570). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Li-Fraumeni syndrome 1 Pathogenic:1
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21059199, 10864200, 25896519, 1467311, 11420676]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 11420676, 1467311, Myriad internal data]. -
Adrenocortical carcinoma, hereditary Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The c.375G>C pathogenic mutation (also known as p.T125T), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 375. This nucleotide substitution does not change the codon at 125. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This variant has been previously detected in a 2-year-old male diagnosed with an ependymoma, with a family history of osteosarcoma and early-onset breast cancer (Chompret A et al. Br. J. Cancer. 2000 Jun;82:1932-7). This variant has also been reported in an individual diagnosed with breast cancer at age 27 (Heymann S et al. Radiat Oncol. 2010 Nov;5:104). A similar variant that leads to the same protein impact, c.375G>A (p.T125T), has been reported in multiple individuals with early-onset cancers whose family histories were suspicious for LFS (Mouchawar J et al. Cancer Res. 2010 Jun;70:4795-800; Fang Z et al. BMC Pediatr. 2021 12;21:588), and was found to lead to partial exon skipping in one RNA study (Rofes P et al. J Mol Diagn. 2020 12;22:1453-1468). Another pathogenic alteration impacting the same site, c.375G>T (p.T125T), has been reported in multiple unrelated families meeting LFS diagnostic criteria and has been shown to lead to aberrant splicing and the use of a cryptic splice site (Varley JM et al. Oncogene. 2001 May;20:2647-54; Mouchawar J et al. Cancer Res. 2010 Jun;70:4795-800; Leroy B et al. Hum. Mutat. 2014 Jun;35:756-65). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
TP53-related disorder Pathogenic:1
The TP53 c.375G>C variant is not predicted to result in an amino acid change (p.=). This variant occurs at the last nucleotide position of exon 4 and is predicted to weaken the adjacent canonical splice donor based on available splicing prediction programs (Alamut Visual Plus v1.6.1). This variant has been reported in a 2 year old individual with a personal and family history suspicious for Li-Fraumeni syndrome (LFS; Family 2471, Tables 3 and 4, Chompret et al. 2000. PubMed ID: 10864200). It has also been reported in an individual with early onset breast cancer (Table 1, Heymann et al. 2010. PubMed ID: 21059199) Assessment using a yeast-based assay suggests this variant leads to retention of 10 nucleotides from intron 4 (Tables 3, Chompret et al. 2000. PubMed ID: 10864200). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/480746/). Alternate nucleotide changes at the same nucleotide position (c.375G>A and c.375G>T) have been implicated in LFS and demonstrated to impact splicing (Figure 3, Warneford et al. 1992. PubMed ID: 1467311; Varley et al. 2001. PubMed ID: 11420676; Table S3, Soussi et al. 2019. PubMed ID: 30720243; Table 1, Rofes et al. 2020. PubMed ID: 33011440; ClinVar IDs: 177825 and 237948). The c.375G>C variant is interpreted as pathogenic. -
not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at