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NM_000546.6(TP53):c.770T>G (p.Leu257Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 11, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000130981.5

Allele description [Variation Report for NM_000546.6(TP53):c.770T>G (p.Leu257Arg)]

NM_000546.6(TP53):c.770T>G (p.Leu257Arg)

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.770T>G (p.Leu257Arg)
HGVS:
  • NC_000017.11:g.7674193A>C
  • NG_017013.2:g.18358T>G
  • NM_000546.6:c.770T>GMANE SELECT
  • NM_001126112.3:c.770T>G
  • NM_001126113.3:c.770T>G
  • NM_001126114.3:c.770T>G
  • NM_001126115.2:c.374T>G
  • NM_001126116.2:c.374T>G
  • NM_001126117.2:c.374T>G
  • NM_001126118.2:c.653T>G
  • NM_001276695.3:c.653T>G
  • NM_001276696.3:c.653T>G
  • NM_001276697.3:c.293T>G
  • NM_001276698.3:c.293T>G
  • NM_001276699.3:c.293T>G
  • NM_001276760.3:c.653T>G
  • NM_001276761.3:c.653T>G
  • NP_000537.3:p.Leu257Arg
  • NP_000537.3:p.Leu257Arg
  • NP_001119584.1:p.Leu257Arg
  • NP_001119585.1:p.Leu257Arg
  • NP_001119586.1:p.Leu257Arg
  • NP_001119587.1:p.Leu125Arg
  • NP_001119588.1:p.Leu125Arg
  • NP_001119589.1:p.Leu125Arg
  • NP_001119590.1:p.Leu218Arg
  • NP_001263624.1:p.Leu218Arg
  • NP_001263625.1:p.Leu218Arg
  • NP_001263626.1:p.Leu98Arg
  • NP_001263627.1:p.Leu98Arg
  • NP_001263628.1:p.Leu98Arg
  • NP_001263689.1:p.Leu218Arg
  • NP_001263690.1:p.Leu218Arg
  • LRG_321t1:c.770T>G
  • LRG_321:g.18358T>G
  • LRG_321p1:p.Leu257Arg
  • NC_000017.10:g.7577511A>C
  • NM_000546.4:c.770T>G
  • NM_000546.5:c.770T>G
  • P04637:p.Leu257Arg
  • p.L257R
Protein change:
L125R
Links:
UniProtKB: P04637#VAR_045285; dbSNP: rs28934577
NCBI 1000 Genomes Browser:
rs28934577
Molecular consequence:
  • NM_000546.6:c.770T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.770T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.770T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.770T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.374T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.374T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.374T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.653T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.653T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.653T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.293T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.293T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.293T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.653T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.653T>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
SCV000185898Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Dec 11, 2019) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From Ambry Genetics, SCV000185898.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.L257R variant (also known as c.770T>G) is located in exon 7 of the TP53 gene. This alteration results from a T to G substitution at nucleotide position 770. The leucine at codon 257 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 capacity and predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):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 was classified as pathogenic based on an evidence-based quantitative model including in silico data and information from IARC regarding somatic-to-germline ratio of specific TP53 variants (Fortuno C et al. Hum. Mutat. 2019 06;40(6):788-800). In addition, another alteration at this codon (p.L257Q) has been previously reported in an individual with multiple primary tumors whose family satisfied clinical diagnostic criteria for Li-Fraumeni syndrome (Mazoyer S et al. Oncogene 1994 Apr;9(4):1237-9 ). 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 majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 29, 2024