NM_000546.6(TP53):c.107C>T (p.Pro36Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Dec 27, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001009836.8

Allele description [Variation Report for NM_000546.6(TP53):c.107C>T (p.Pro36Leu)]

NM_000546.6(TP53):c.107C>T (p.Pro36Leu)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.107C>T (p.Pro36Leu)

HGVS:

NC_000017.11:g.7676262G>A
NG_017013.2:g.16289C>T
NM_000546.6:c.107C>TMANE SELECT
NM_001126112.3:c.107C>T
NM_001126113.3:c.107C>T
NM_001126114.3:c.107C>T
NM_001126118.2:c.-11C>T
NM_001276695.3:c.-11C>T
NM_001276696.3:c.-11C>T
NM_001276760.3:c.-11C>T
NM_001276761.3:c.-11C>T
NP_000537.3:p.Pro36Leu
NP_001119584.1:p.Pro36Leu
NP_001119585.1:p.Pro36Leu
NP_001119586.1:p.Pro36Leu
LRG_321:g.16289C>T
NC_000017.10:g.7579580G>A
NC_000017.10:g.7579580G>A
NM_000546.4:c.107C>T

Protein change:

P36L

Links:

dbSNP: rs587781866

NCBI 1000 Genomes Browser:

rs587781866

Molecular consequence:

NM_001126118.2:c.-11C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276695.3:c.-11C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276696.3:c.-11C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276760.3:c.-11C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276761.3:c.-11C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.107C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.107C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.107C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.107C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001169952	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 27, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 28861920, 30224644 Citation Link,
SCV002582160	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005402690	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	criteria provided, single submitter (Dawood et al. (medRxiv. 2024))	Likely Benign (Apr 12, 2024)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 33300245, 34793697, 38645101

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001169952

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 27, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002582160

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 18, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005402690

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

criteria provided, single submitter

(Dawood et al. (medRxiv. 2024))

Likely Benign
(Apr 12, 2024)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C.

Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Epub 2003 Jun 25.

PubMed [citation]

PMID:: 12826609
PMCID:: PMC166245

Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history.

de Andrade KC, Mirabello L, Stewart DR, Karlins E, Koster R, Wang M, Gapstur SM, Gaudet MM, Freedman ND, Landi MT, Lemonnier N, Hainaut P, Savage SA, Achatz MI.

Hum Mutat. 2017 Dec;38(12):1723-1730. doi: 10.1002/humu.23320. Epub 2017 Sep 21.

PubMed [citation]

PMID:: 28861920
PMCID:: PMC6858060

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV001169952.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.P36L variant (also known as c.107C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 107. The proline at codon 36 is replaced by leucine, an amino acid with similar properties. Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat Genet, 2018 Oct;50:1381-1387). This variant is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc Natl Acad Sci U S A, 2003 Jul;100:8424-9). This amino acid position is poorly conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002582160.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV005402690.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

Description

Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For TP53, we used the output of the Naïve Bayes classifier that synthesized data from four different TP53 MAVEs in Fayer et al. (2021) (PMID: 34793697). If the classifier predicted a variant to be "Functionally abnormal," the variant was assigned PS3 evidence and no BS3 evidence. If a variant was predicted to be "Functionally normal," BS3_moderate evidence was used with no PS3 evidence. This variant GRCh37:17:7579580:G>A was assigned evidence codes ['BS3_Moderate', 'BP4'] and an overall classification of Likely Benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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