VCV000012369.20 - ClinVar

NM_000546.6(TP53):c.451C>A (p.Pro151Thr)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (3); Likely pathogenic (4)

7 out of 9 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.451C>A (p.Pro151Thr)

Variation ID: 12369 Accession: VCV000012369.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7675161 (GRCh38) [ NCBI UCSC ] 17: 7578479 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Feb 15, 2026	Apr 18, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.451C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Pro151Thr	missense
NM_001126112.3:c.451C>A	NP_001119584.1:p.Pro151Thr	missense
NM_001126113.3:c.451C>A	NP_001119585.1:p.Pro151Thr	missense
NM_001126114.3:c.451C>A	NP_001119586.1:p.Pro151Thr	missense
NM_001126115.2:c.55C>A	NP_001119587.1:p.Pro19Thr	missense
NM_001126116.2:c.55C>A	NP_001119588.1:p.Pro19Thr	missense
NM_001126117.2:c.55C>A	NP_001119589.1:p.Pro19Thr	missense
NM_001126118.2:c.334C>A	NP_001119590.1:p.Pro112Thr	missense
NM_001276695.3:c.334C>A	NP_001263624.1:p.Pro112Thr	missense
NM_001276696.3:c.334C>A	NP_001263625.1:p.Pro112Thr	missense
NM_001276697.3:c.-27C>A		5 prime UTR
NM_001276698.3:c.-27C>A		5 prime UTR
NM_001276699.3:c.-27C>A		5 prime UTR
NM_001276760.3:c.334C>A	NP_001263689.1:p.Pro112Thr	missense
NM_001276761.3:c.334C>A	NP_001263690.1:p.Pro112Thr	missense
NC_000017.11:g.7675161G>T
NC_000017.10:g.7578479G>T
NG_017013.2:g.17390C>A
LRG_321:g.17390C>A
LRG_321t1:c.451C>A	LRG_321p1:p.Pro151Thr
	P04637:p.Pro151Thr

... more HGVS ... less HGVS

Protein change

P151T, P112T, P19T

Other names

Canonical SPDI

NC_000017.11:7675160:G:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA000198 UniProtKB: P04637#VAR_005896 OMIM: 191170.0025 dbSNP: rs28934874 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TP53		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3915	4016

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Breast adenocarcinoma	Pathogenic (1)	no assertion criteria provided	Jul 1, 1993	RCV000013168.8
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 21, 2024	RCV000130617.11
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 4, 2025	RCV000520731.5
Li-Fraumeni syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 18, 2025	RCV000691152.13
Rhabdomyosarcoma	Pathogenic (1)	no assertion criteria provided	Sep 1, 2020	RCV001257524.5
Li-Fraumeni syndrome 1	Likely pathogenic (1)	criteria provided, single submitter	Jun 18, 2022	RCV002288486.5
Adrenocortical carcinoma, hereditary	Likely pathogenic (1)	criteria provided, single submitter	Dec 14, 2023	RCV004566739.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004026691.2 First in ClinVar: Aug 19, 2023 Last updated: Mar 11, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Aug 24, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000617735.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Comment: show This variant is denoted TP53 c.451C>A at the cDNA level, p.Pro151Thr (P151T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). This variant has been observed in two individuals with early-onset breast cancer, one of whom had a family history of sarcoma and adrenocortical carcinoma (Vahteristo 2001, Maxwell 2015). Although this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), and Monti et al. (2011) also found a significant reduction in transactivation activity, this variant was not found to cause a dominant-negative effect and only had a slight impact on growth suppression (Monti 2011, Kotler 2018). TP53 Pro151Thr was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider TP53 Pro151Thr to be a likely pathogenic variant. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jun 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Genome-Nilou Lab Accession: SCV002582396.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Likely pathogenic (Jun 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Li-Fraumeni syndrome 1	Genome-Nilou Lab Accession: SCV002583058.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Nov 21, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000185493.10 First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025	Publications: PubMed (5) PubMed: 11479205‚ 12826609‚ 25503501‚ 29979965‚ 30224644 Comment: show The p.P151T pathogenic mutation (also known as c.451C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 451. The proline at codon 151 is replaced by threonine, an amino acid with highly similar properties. This mutation has been reported in several families meeting clinical criteria for Li-Fraumeni Syndrome (LFS) (Vahteristo P et al. Cancer Res. 2001; 61:5718-22; Ambry internal data). This variant was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). 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). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Dec 14, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Adrenocortical carcinoma, hereditary	Baylor Genetics Accession: SCV005054344.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Apr 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Li-Fraumeni syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000818896.8 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (13) PubMed: 10713666‚ 11479205‚ 12826609‚ 16861262‚ 20128691‚ 20522432‚ 21343334‚ 23625637‚ 25503501‚ 28492532‚ 29979965‚ 30224644‚ 7881428 Comment: show This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 151 of the TP53 protein (p.Pro151Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with early-onset breast cancer and TP53-related disease (PMID: 11479205, 25503501). ClinVar contains an entry for this variant (Variation ID: 12369). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). This variant disrupts the p.Pro151 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7881428, 10713666, 12826609, 16861262, 20128691, 20522432, 21343334, 23625637). 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jul 01, 1993) N Not contributing to aggregate classification	no assertion criteria provided	BREAST CANCER, SOMATIC	OMIM Accession: SCV000033415.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 8364550 Observation: 1 Collection method: literature only Allele origin: somatic Affected status: not provided more Observation 1 Collection method: literature only Allele origin: somatic Affected status: not provided Comment on evidence: In a breast cancer (114480), Carrere et al. (1993) identified a CCC-to-ACC transversion in codon 151 of the p53 gene, resulting in a substitution of … (more) In a breast cancer (114480), Carrere et al. (1993) identified a CCC-to-ACC transversion in codon 151 of the p53 gene, resulting in a substitution of proline by threonine (P151T). (less)

Pathogenic (Sep 01, 2020) N Not contributing to aggregate classification	no assertion criteria provided	Rhabdomyosarcoma	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434350.1 First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020	Observation: 1 Collection method: provider interpretation Allele origin: germline Affected status: yes Observation 1 Collection method: provider interpretation Allele origin: germline Affected status: yes

Comment:

This variant is denoted TP53 c.451C>A at the cDNA level, p.Pro151Thr (P151T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). This variant has been observed in two individuals with early-onset breast cancer, one of whom had a family history of sarcoma and adrenocortical carcinoma (Vahteristo 2001, Maxwell 2015). Although this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), and Monti et al. (2011) also found a significant reduction in transactivation activity, this variant was not found to cause a dominant-negative effect and only had a slight impact on growth suppression (Monti 2011, Kotler 2018). TP53 Pro151Thr was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider TP53 Pro151Thr to be a likely pathogenic variant.

Comment:

The p.P151T pathogenic mutation (also known as c.451C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 451. The proline at codon 151 is replaced by threonine, an amino acid with highly similar properties. This mutation has been reported in several families meeting clinical criteria for Li-Fraumeni Syndrome (LFS) (Vahteristo P et al. Cancer Res. 2001; 61:5718-22; Ambry internal data). This variant was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). 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). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a 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 was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 151 of the TP53 protein (p.Pro151Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with early-onset breast cancer and TP53-related disease (PMID: 11479205, 25503501). ClinVar contains an entry for this variant (Variation ID: 12369). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). This variant disrupts the p.Pro151 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7881428, 10713666, 12826609, 16861262, 20128691, 20522432, 21343334, 23625637). 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.	Li H	Journal of the National Cancer Institute	2021	PMID: 33372952
Mutational processes shape the landscape of TP53 mutations in human cancer.	Giacomelli AO	Nature genetics	2018	PMID: 30224644
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.	Kotler E	Molecular cell	2018	PMID: 29979965
Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer.	Maxwell KN	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25503501
Serine substitution of proline at codon 151 of TP53 confers gain of function activity leading to anoikis resistance and tumor progression of head and neck cancer cells.	Xie TX	The Laryngoscope	2013	PMID: 23625637
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.	Monti P	Molecular cancer research : MCR	2011	PMID: 21343334
TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes.	Ruijs MW	Journal of medical genetics	2010	PMID: 20522432
Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation.	Malcikova J	Biological chemistry	2010	PMID: 20128691
Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.	Dearth LR	Carcinogenesis	2007	PMID: 16861262
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.	Kato S	Proceedings of the National Academy of Sciences of the United States of America	2003	PMID: 12826609
p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.	Vahteristo P	Cancer research	2001	PMID: 11479205
Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy.	Bullock AN	Oncogene	2000	PMID: 10713666
A de novo p53 germline mutation affecting codon 151 in a six year old child with multiple tumors.	Gutiérrez MI	Human molecular genetics	1994	PMID: 7881428
A new mutation of exon 5 of the P53 gene in breast cancer.	Carrere N	Human molecular genetics	1993	PMID: 8364550
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Text-mined citations for rs28934874 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026