NM_000546.6(TP53):c.760A>G (p.Ile254Val) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Jul 13, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000546.6(TP53):c.760A>G (p.Ile254Val)]

NM_000546.6(TP53):c.760A>G (p.Ile254Val)

TP53:tumor protein p53 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000546.6(TP53):c.760A>G (p.Ile254Val)
Other names:
NM_000546.5(TP53):c.760A>G; p.Ile254Val
  • NC_000017.11:g.7674203T>C
  • NC_000017.11:g.7674203T>C
  • NG_017013.2:g.18348A>G
  • NM_000546.5:c.760A>G
  • NM_000546.6:c.760A>GMANE SELECT
  • NM_001126112.3:c.760A>G
  • NM_001126113.3:c.760A>G
  • NM_001126114.3:c.760A>G
  • NM_001126115.2:c.364A>G
  • NM_001126116.2:c.364A>G
  • NM_001126117.2:c.364A>G
  • NM_001126118.2:c.643A>G
  • NM_001276695.3:c.643A>G
  • NM_001276696.3:c.643A>G
  • NM_001276697.3:c.283A>G
  • NM_001276698.3:c.283A>G
  • NM_001276699.3:c.283A>G
  • NM_001276760.3:c.643A>G
  • NM_001276761.3:c.643A>G
  • NP_000537.3:p.Ile254Val
  • NP_000537.3:p.Ile254Val
  • NP_001119584.1:p.Ile254Val
  • NP_001119585.1:p.Ile254Val
  • NP_001119586.1:p.Ile254Val
  • NP_001119587.1:p.Ile122Val
  • NP_001119588.1:p.Ile122Val
  • NP_001119589.1:p.Ile122Val
  • NP_001119590.1:p.Ile215Val
  • NP_001263624.1:p.Ile215Val
  • NP_001263625.1:p.Ile215Val
  • NP_001263626.1:p.Ile95Val
  • NP_001263627.1:p.Ile95Val
  • NP_001263628.1:p.Ile95Val
  • NP_001263689.1:p.Ile215Val
  • NP_001263690.1:p.Ile215Val
  • LRG_321t1:c.760A>G
  • LRG_321:g.18348A>G
  • LRG_321p1:p.Ile254Val
  • NC_000017.10:g.7577521T>C
  • NC_000017.10:g.7577521T>C
  • NM_000546.4:c.760A>G
Protein change:
dbSNP: rs746601313
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000546.5:c.760A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000546.6:c.760A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.760A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.760A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.760A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.364A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.364A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.364A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.643A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.643A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.643A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.283A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.283A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.283A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.643A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.643A>G - missense variant - [Sequence Ontology: SO:0001583]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000664384Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jan 7, 2020)
germlineclinical testing

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

Citation Link,

SCV000686769Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jul 13, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome.

Foulkes WD, Chappuis PO, Wong N, Brunet JS, Vesprini D, Rozen F, Yuan ZQ, Pollak MN, Kuperstein G, Narod SA, B├ęgin LR.

Ann Oncol. 2000 Mar;11(3):307-13.

PubMed [citation]

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]
See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV000664384.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (9)


The p.I254V variant (also known as c.760A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 760. The isoleucine at codon 254 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in one family with a "certain probability of having LFS," however, no details were provided regarding this family's medical history (Foretova L et al. Klin Onkol 2010;23(6):388-400). This alteration has also been reported as a somatic alteration in a variety of tumor types (Foulkes WD et. al. Ann. Oncol. 2000 Mar;11(3):307-13; Chiaretti S et al. Haematologica 2013 May;98(5):e59-61; Starr JS et al. J. Clin. Oncol. 2015 Jun; 33(17):e74-6). In addition, a similar alteration at this position, p.I254T, was reported in a woman from a LFS family with breast cancer at age 36 (Patrier-Sallebert S et al. J. Med. Genet. 2015 Mar;52(3):145-6). The p.I254V variant is in the DNA binding domain of the TP53 protein and is predicted to affect several p53 isoforms; however, it is reported to have functional transactivation capacity (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additionally, studies conducted in human cell lines indicate this alteration remains proficient 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 amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000686769.4

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


This missense variant replaces isoleucine with valine at codon 254 of the TP53 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant does not impair TP53 protein function (PMID: 12826609, 30224644). This variant is said to be reported in a family affected with Li-Fraumeni syndrome but detailed clinical findings were not provided for evaluation (PMID: 21348412). This variant has been reported in individuals affected with non-small cell lung cancer (PMID: 27242894) and uveal melanoma (PMID: 29769598), as well as in control individuals unaffected with cancer (PMID: 28861920). This variant has been identified in 4/251476 individuals the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 25, 2021

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