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NM_000546.6(TP53):c.833C>G (p.Pro278Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
May 22, 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:
RCV000572417.8

Allele description [Variation Report for NM_000546.6(TP53):c.833C>G (p.Pro278Arg)]

NM_000546.6(TP53):c.833C>G (p.Pro278Arg)

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.833C>G (p.Pro278Arg)
HGVS:
  • NC_000017.11:g.7673787G>C
  • NG_017013.2:g.18764C>G
  • NM_000546.6:c.833C>GMANE SELECT
  • NM_001126112.3:c.833C>G
  • NM_001126113.3:c.833C>G
  • NM_001126114.3:c.833C>G
  • NM_001126115.2:c.437C>G
  • NM_001126116.2:c.437C>G
  • NM_001126117.2:c.437C>G
  • NM_001126118.2:c.716C>G
  • NM_001276695.3:c.716C>G
  • NM_001276696.3:c.716C>G
  • NM_001276697.3:c.356C>G
  • NM_001276698.3:c.356C>G
  • NM_001276699.3:c.356C>G
  • NM_001276760.3:c.716C>G
  • NM_001276761.3:c.716C>G
  • NP_000537.3:p.Pro278Arg
  • NP_000537.3:p.Pro278Arg
  • NP_001119584.1:p.Pro278Arg
  • NP_001119585.1:p.Pro278Arg
  • NP_001119586.1:p.Pro278Arg
  • NP_001119587.1:p.Pro146Arg
  • NP_001119588.1:p.Pro146Arg
  • NP_001119589.1:p.Pro146Arg
  • NP_001119590.1:p.Pro239Arg
  • NP_001263624.1:p.Pro239Arg
  • NP_001263625.1:p.Pro239Arg
  • NP_001263626.1:p.Pro119Arg
  • NP_001263627.1:p.Pro119Arg
  • NP_001263628.1:p.Pro119Arg
  • NP_001263689.1:p.Pro239Arg
  • NP_001263690.1:p.Pro239Arg
  • LRG_321t1:c.833C>G
  • LRG_321:g.18764C>G
  • LRG_321p1:p.Pro278Arg
  • NC_000017.10:g.7577105G>C
  • NM_000546.4:c.833C>G
  • NM_000546.5:c.833C>G
Protein change:
P119R
Links:
dbSNP: rs876659802
NCBI 1000 Genomes Browser:
rs876659802
Molecular consequence:
  • NM_000546.6:c.833C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.833C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.833C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.833C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.437C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.437C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.437C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.716C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.716C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.716C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.356C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.356C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.356C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.716C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.716C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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    Assertion and evidence details

    Help
    Submission AccessionSubmitterReview Status
    (Assertion method)    		Clinical Significance
    (Last evaluated)    		OriginMethodCitations
    SCV000672393Ambry Genetics
    criteria provided, single submitter

    (Ambry Variant Classification Scheme 2023)    		Pathogenic
    (May 22, 2024)     		germlineclinical testing

    PubMed (9)
    [See all records that cite these PMIDs]

    Citation Link,

    SCV002581993Genome-Nilou Lab
    criteria provided, single submitter

    (ACMG Guidelines, 2015)    		Uncertain significance
    (Jun 18, 2022)     		germlineclinical testing

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

    Help

    Summary from all submissions

    EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
    not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
    not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

    Citations

    PubMed

    Prognostic value of p53 molecular status in high-risk primary breast cancer.

    Marchetti P, Cannita K, Ricevuto E, De Galitiis F, Di Rocco ZC, Tessitore A, Bisegna R, Porzio G, De Rubeis GP, Ventura T, Martinotti S, Ficorella C.

    Ann Oncol. 2003 May;14(5):704-8.

    PubMed [citation]
    PMID:
    12702523

    Spectrum of p53 mutations in biopsies from breast cancer patients selected for preoperative chemotherapy analysed by the functional yeast assay to predict therapeutic response.

    Deissler H, Kafka A, Schuster E, Sauer G, Kreienberg R, Zeillinger R.

    Oncol Rep. 2004 Jun;11(6):1281-6.

    PubMed [citation]
    PMID:
    15138567
    See all PubMed Citations (10)

    Details of each submission

    From Ambry Genetics, SCV000672393.6

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedclinical testing PubMed (9)

    Description

    The p.P278R pathogenic mutation (also known as c.833C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 833. The proline at codon 278 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of 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 (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Other alterations at this same amino acid position (p.P278A, p.P278S, p.P278T) have previously been reported in the germline of individuals diagnosed with Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2001 Apr; 38(4):253-7; Güran S et al. Cancer Genet. Cytogenet. 2005 Jul; 160(2):164-8; Speiser P et al. Br. J. Cancer 1996 Jul; 74(2):269-73). 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 variant is interpreted as a disease-causing mutation.

    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

    From Genome-Nilou Lab, SCV002581993.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedclinical testing PubMed (1)
    #SampleMethodObservation
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1germlinenonot providednot providednot providednot providednot providednot providednot provided

    Last Updated: Sep 29, 2024