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

gnomAD frequency: 0.00001  dbSNP: rs55863639

Total submissions: 19

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	RCV000154460	SCV000697430	pathogenic	Li-Fraumeni syndrome	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.375G>A (p.Thr125Thr) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant was absent in 250746 control chromosomes. c.375G>A has been reported in the literature as co-segregating with disease in multiple individuals affected with Li-Fraumeni Syndrome/Li-Fraunemi like Syndrome (example, Varley_1998, Warneford_1992, Wasserman_2015) as well in settings of somatic malignancies. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle (Varley_1998). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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 condition	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.
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