ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.375G>A (p.Thr125=)

gnomAD frequency: 0.00001  dbSNP: rs55863639
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218743 SCV000277767 pathogenic Hereditary cancer-predisposing syndrome 2022-03-14 criteria provided, single submitter clinical testing The c.375G>A pathogenic mutation (also known as p.T125T), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 375. This nucleotide substitution does not change the threonine at codon 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 mutation has been reported in numerous patients and families meeting Li-Fraumeni, Li-Fraumeni-like, and Chompret criteria (Varley JM et al. Cancer Res. 1997 Aug;57:3245-3252; Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; Mouchawar J et al. Cancer Res. 2010 Jun 15;70(12):4795-800; Foretova L et al. Klin. Onkol. 2010;23:388-400; Herrmann LJ et al. J. Clin. Endocrinol. Metab. 2012 Mar;97(3):E476-85; Hettmer S et al. Cancer. 2014 Apr 1;120(7):1068-75; Fortes FP et al. Braz. J. Med. Biol. Res. 2015 Jul;48(7):610-5; Gröbner SN et al. Nature. 2018 03;555(7696):321-327). Of note, this alteration is also designated as g.12299G>A in published literature. One study showed evidence of intron 3 retention in affected individuals with this mutation (Warneford SG et al. Cell Growth Differ. 1992 Nov;3(11):839-46) and this is supported by our internal RNA studies (Ambry internal data). 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.
GeneDx RCV000483667 SCV000567386 pathogenic not provided 2023-07-11 criteria provided, single submitter clinical testing Published functional studies demonstrate aberrant splicing, impaired transactivation, abnormal cellular localization, and loss of growth suppression ability (Warneford 1992, Varley 1997, Varley 2001, Kotler 2018, Lasham 2020, Pinto 2021); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 1467311, 28818333, 32504368, 34282142, 20501846, 22170717, 18511570, 24665023, 20522432, 26425688, 25525159, 24382691, 9242456, 1751410, 25584008, 1961027, 11420676, 23259501, 28347348, 29170254, 28026089, 28604612, 25945745, 29489754, 29979965, 30107858, 31439692, 32213968, 32888145, 30720243, 31105275, 32287321, 26582918, 33818021, 33011440, 33372952, 34539730, 33245408, 32427313, 34961499, 35512711, 37377903, 9681828, 30612635, 34887416, 34675114, Almeida2022[article], 35543639, 36428697, 15510160)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483667 SCV000602269 pathogenic not provided 2017-02-15 criteria provided, single submitter clinical testing
Invitae RCV000154460 SCV000629813 pathogenic Li-Fraumeni syndrome 2023-12-28 criteria provided, single submitter 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 1467311, 9242456, 11420676, 18511570, 21348412, 22170717, 24382691, 25584008, 25945745, 27501770). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177825). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 1467311, 11420676). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004525830 SCV000697430 pathogenic Nephrogenic diabetes insipidus 2020-10-26 criteria provided, single submitter clinical testing Variant summary: AQP2 c.375G>A alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.5e-05 in 241810 control chromosomes, predominantly at a frequency of 8.8e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 281.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in AQP2 causing Nephrogenic Diabetes Insipidus phenotype (3.1e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.375G>A in individuals affected with Nephrogenic Diabetes Insipidus and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000483667 SCV001450280 pathogenic not provided 2015-06-23 criteria provided, single submitter clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital RCV001530197 SCV001739492 pathogenic Glioma susceptibility 1 2020-02-28 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000218743 SCV002582609 pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002288665 SCV002583171 pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003398806 SCV004111187 pathogenic TP53-related disorder 2022-12-19 criteria provided, single submitter clinical testing The TP53 c.375G>A variant is not predicted to result in an amino acid change (p.=). This variant is predicted to strongly reduce the stregth of the neighboring splice donor site. This variant has been reported in several individuals with Li-Fraumeni and Li-Fraumeni-like syndrome (see for example, Warneford et al 1992. PubMed ID: 1467311; Wasserman JD et al 2015. PubMed ID: 25584008). These studies and others provide evidence that this variant segregates with disease in families and disrupts TP53 splicing. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is classified as pathogenic by several laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/177825/). We also clasify this variant as patogenic.
Baylor Genetics RCV003462060 SCV004206208 pathogenic Adrenocortical carcinoma, hereditary 2023-10-29 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000218743 SCV004360011 pathogenic Hereditary cancer-predisposing syndrome 2023-02-21 criteria provided, single submitter clinical testing This variant alters the highly conserved, last nucleotide c.G in exon 4 of the TP53 gene and is predicted to abolish intron 4 splice donor site. This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 9242456, 11420676, 30107858), rhabdomyosarcoma (PMID: 24382691, 27501770, 33372952) and adrenocortical carcinoma (PMID: 22170717, 25584008), as well as in a family with Li-Fraumeni-like syndrome with an unusual spectrum of tumors at relatively late onset (PMID: 9681828). RT-PCR analysis of mRNA from the carriers in this family has detected no normally spliced transcript but three different aberrantly spliced transcripts from the mutant TP53 allele. All three aberrant transcripts are predicted to result in premature protein truncation (PMID: 9681828). Cells from the carriers showed increased sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle, and decreased transient and permanent G1 arrest (PMID: 9681828). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health RCV000154460 SCV004823813 pathogenic Li-Fraumeni syndrome 2023-04-24 criteria provided, single submitter clinical testing This variant alters the highly conserved, last nucleotide c.G in exon 4 of the TP53 gene and is predicted to abolish intron 4 splice donor site. This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 9242456, 11420676, 30107858), rhabdomyosarcoma (PMID: 24382691, 27501770, 33372952) and adrenocortical carcinoma (PMID: 22170717, 25584008), as well as in a family with Li-Fraumeni-like syndrome with an unusual spectrum of tumors at relatively late onset (PMID: 9681828). RT-PCR analysis of mRNA from the carriers in this family has detected no normally splice transcript but three different aberrantly spliced transcripts from the mutant TP53 allele. All three aberrant transcripts are predicted to result in premature protein truncation (PMID: 9681828). Cells from the carriers showed increased sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle, and decreased transient and permanent G1 arrest (PMID: 9681828). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc. RCV002288665 SCV004933123 likely pathogenic Li-Fraumeni syndrome 1 2024-02-13 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1467311, 11420676]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 1467311, 11420676, Myriad internal data].
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154460 SCV000204129 pathogenic Li-Fraumeni syndrome 2008-07-31 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000483667 SCV000692091 pathogenic not provided no assertion criteria provided clinical testing
MutSpliceDB: a database of splice sites variants effects on splicing, NIH RCV000483667 SCV000925737 not provided not provided no assertion provided in vitro
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001257525 SCV001434351 pathogenic Rhabdomyosarcoma 2020-09-01 no assertion criteria provided provider interpretation
CZECANCA consortium RCV001271053 SCV001451872 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
University Health Network, Princess Margaret Cancer Centre RCV001527480 SCV001738499 pathogenic Malignant tumor of prostate 2021-03-19 no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000218743 SCV002589023 pathogenic Hereditary cancer-predisposing syndrome 2022-08-26 no assertion criteria provided clinical testing

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