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NM_000546.6(TP53):c.145G>C (p.Asp49His) AND Li-Fraumeni syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 11, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000123095.16

Allele description [Variation Report for NM_000546.6(TP53):c.145G>C (p.Asp49His)]

NM_000546.6(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_000546.6(TP53):c.145G>C (p.Asp49His)
HGVS:
  • NC_000017.11:g.7676224C>G
  • NG_017013.2:g.16327G>C
  • NM_000546.6:c.145G>CMANE SELECT
  • NM_001126112.3:c.145G>C
  • NM_001126113.3:c.145G>C
  • NM_001126114.3:c.145G>C
  • NM_001126118.2:c.28G>C
  • NM_001276695.3:c.28G>C
  • NM_001276696.3:c.28G>C
  • NM_001276760.3:c.28G>C
  • NM_001276761.3:c.28G>C
  • NP_000537.3:p.Asp49His
  • 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_321:g.16327G>C
  • LRG_321p1:p.Asp49His
  • NC_000017.10:g.7579542C>G
  • NM_000546.4:c.145G>C
  • NM_000546.5: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_000546.6:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.28G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Li-Fraumeni syndrome (LFS)
Synonyms:
Sarcoma family syndrome of Li and Fraumeni
Identifiers:
MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000166395Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 11, 2024) 		germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV004823845All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(May 31, 2023) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines.

Ohmoto A, Morizane C, Kubo E, Takai E, Hosoi H, Sakamoto Y, Kondo S, Ueno H, Shimada K, Yachida S, Okusaka T.

J Gastroenterol. 2018 Oct;53(10):1159-1167. doi: 10.1007/s00535-018-1466-y. Epub 2018 Apr 17.

PubMed [citation]
PMID:
29667044

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]
PMID:
30287823
PMCID:
PMC6172276
See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000166395.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 49 of the TP53 protein (p.Asp49His). This variant is present in population databases (rs587780728, gnomAD 0.01%). This missense change has been observed in individual(s) with sarcoma, lymphoma, pancreatic cancer, prostate cancer, biliary tract cancer, and/or breast cancer (PMID: 27545002, 28902083, 29667044, 30287823, 34863587). ClinVar contains an entry for this variant (Variation ID: 135948). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9207066, 12826609, 12901974, 15489903, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From All of Us Research Program, National Institutes of Health, SCV004823845.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (8)

Description

This missense variant replaces aspartic acid with histidine at codon 49 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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), 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: Sep 29, 2024