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

Genomes: not found (cov: 32)

Consequence

TP53
NM_000546.6 splice_region, synonymous

Scores

2
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: -0.0700
Variant links:
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-7675994-C-G is Pathogenic according to our data. Variant chr17-7675994-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 480746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.375G>C p.Thr125Thr splice_region_variant, synonymous_variant Exon 4 of 11 ENST00000269305.9 NP_000537.3 P04637-1K7PPA8Q53GA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkc.375G>C p.Thr125Thr splice_region_variant, synonymous_variant Exon 4 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:1
Dec 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 14, 2024
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 23, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Hereditary cancer-predisposing syndrome Pathogenic:1
Oct 31, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Mar 08, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Significance: not provided
Review Status: no classification provided
Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.25
CADD
Benign
22
DANN
Benign
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.87
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.24
Position offset: -48
DS_DL_spliceai
0.87
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs55863639; hg19: chr17-7579312; COSMIC: COSV53120615; COSMIC: COSV53120615; API