NM_000546.5(TP53):c.145G>C (p.Asp49His) AND Hereditary cancer-predisposing syndrome

Clinical significance:Uncertain significance (Last evaluated: Aug 20, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000129275.7

Allele description [Variation Report for NM_000546.5(TP53):c.145G>C (p.Asp49His)]

NM_000546.5(TP53):c.145G>C (p.Asp49His)

Gene:
TP53:tumor protein p53 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000546.5(TP53):c.145G>C (p.Asp49His)
HGVS:
  • NC_000017.11:g.7676224C>G
  • NG_017013.2:g.16327G>C
  • NM_000546.5:c.145G>C
  • NM_001126112.2:c.145G>C
  • NM_001126113.2:c.145G>C
  • NM_001126114.2:c.145G>C
  • NM_001126118.1:c.28G>C
  • NM_001276695.2:c.28G>C
  • NM_001276696.2:c.28G>C
  • NM_001276760.2:c.28G>C
  • NM_001276761.2:c.28G>C
  • NP_000537.3:p.Asp49His
  • NP_001119584.1:p.Asp49His
  • NP_001119585.1:p.Asp49His
  • NP_001119586.1:p.Asp49His
  • NP_001119590.1:p.Asp10His
  • NP_001263624.1:p.Asp10His
  • NP_001263625.1:p.Asp10His
  • NP_001263689.1:p.Asp10His
  • NP_001263690.1:p.Asp10His
  • LRG_321t1:c.145G>C
  • LRG_321t2:c.145G>C
  • LRG_321t3:c.145G>C
  • LRG_321t4:c.145G>C
  • LRG_321t8:c.28G>C
  • LRG_321:g.16327G>C
  • LRG_321:p.Asp49His
  • LRG_321p1:p.Asp49His
  • LRG_321p3:p.Asp49His
  • LRG_321p4:p.Asp49His
  • LRG_321p8:p.Asp10His
  • NC_000017.10:g.7579542C>G
  • NM_000546.4:c.145G>C
  • NM_001126112.2(TP53):c.145G>C
  • P04637:p.Asp49His
  • p.D49H
Protein change:
D10H
Links:
UniProtKB: P04637#VAR_044571; dbSNP: rs587780728
NCBI 1000 Genomes Browser:
rs587780728
Molecular consequence:
  • NM_000546.5:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.2:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.2:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.2:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.1:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.2:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.2:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.2:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.2:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000184035Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Jun 20, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000686722Color Health, Inccriteria provided, single submitter
Uncertain significance
(Aug 20, 2019)
germlineclinical testing

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

Description

This missense variant replaces aspartic acid with histidine at codon 49 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has reported the variant protein to activate VEGF expression and increased growth support in leukemic cells and p53-null cell line (PMID: 12901974). However, yeast studies have reported the variant protein to be non-functional in transcription activation (PMID: 12826609 and IARC database). This variant in combination with p.D48H in TP53 peptide and full-length protein has also been reported to have lost RPA binding and the suppression of homologous recombination (PMID: 9207066, 15489903). This variant has been reported in two individuals diagnosed with Li-Fraumani syndrome (LFS), and one of which has a second TP53 covariant (PMID: 28902083, 27545002). This variant has also been reported in five individuals with cancer history but do not meet the criteria for LFS or Li-Fraumani-like syndrome (PMID: 27545002), and in three individuals affected with sarcoma and in one healthy control (PMID: 1565143). This variant has been identified in 1/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has conflicting reports on functional impact and has been observed in affected individuals as well as in the general population. 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.

SCV000686722

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

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

Mutant p53 in bone marrow stromal cells increases VEGF expression and supports leukemia cell growth.

Narendran A, Ganjavi H, Morson N, Connor A, Barlow JW, Keystone E, Malkin D, Freedman MH.

Exp Hematol. 2003 Aug;31(8):693-701.

PubMed [citation]
PMID:
12901974
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000184035.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The p.D49H variant (also known as c.145G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 145. The aspartic acid at codon 49 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in six patients from a cohort of 1685 Japanese adult patients with various cancers (Yamaguchi K et al. Biomed. Res., 2016;37:259-64). Of these cases, only one of the six met clinical criteria for Li-Fraumeni-Like syndrome (LFL), but this individual was also noted to carry the TP53 p.A159D germline alteration. Further, this alteration has been identified in a 15 year old boy with lymphocyte-predominant Hodgkin lymphoma, and was also identified in his sister who has a history of rhabdomyosarcoma at the age of 1.5 years (Yamazaki F et al. J. Pediatr. Hematol. Oncol. 2017 Sep). This alteration was shown to have a loss of transactivation capacity in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9), and increase VEGF expression in mammalian cells (Narendran A et al. Exp. Hematol. 2003 Aug;31:693-701). This amino acid position is not well conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From Color Health, Inc, SCV000686722.3

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

Last Updated: Jun 23, 2021

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