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NM_000546.6(TP53):c.145G>C (p.Asp49His)

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Interpretation:
Likely benign​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
8 (Most recent: Jun 18, 2021)
Last evaluated:
May 6, 2021
Accession:
VCV000135948.12
Variation ID:
135948
Description:
single nucleotide variant
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NM_000546.6(TP53):c.145G>C (p.Asp49His)

Allele ID
139660
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17p13.1
Genomic location
17: 7676224 (GRCh38) GRCh38 UCSC
17: 7579542 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_321:g.16327G>C
LRG_321t1:c.145G>C LRG_321p1:p.Asp49His
LRG_321t2:c.145G>C
... more HGVS
Protein change
D10H, D49H
Other names
-
Canonical SPDI
NC_000017.11:7676223:C:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA000057
UniProtKB: P04637#VAR_044571
dbSNP: rs587780728
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 3 reviewed by expert panel May 6, 2021 RCV000410497.3
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Aug 20, 2019 RCV000129275.7
Uncertain significance 1 criteria provided, single submitter Oct 21, 2020 RCV000123095.8
Uncertain significance 1 criteria provided, single submitter May 1, 2019 RCV001030740.1
Uncertain significance 1 criteria provided, single submitter Mar 14, 2019 RCV001192616.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TP53 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
2205 2268

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely benign
(May 06, 2021)
reviewed by expert panel
Method: curation
Li-Fraumeni syndrome 1
(Autosomal dominant inheritance)
Allele origin: germline
ClinGen TP53 Variant Curation Expert Panel,ClinGen
FDA Recognized Database
Accession: SCV001737934.1
Submitted: (Jun 18, 2021)
Evidence details
Other databases
https://erepo.clinicalgenome.org…
Comment:
This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been observed in … (more)
Uncertain significance
(Jun 20, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000184035.6
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (6)
Comment:
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 … (more)
Uncertain significance
(Oct 21, 2020)
criteria provided, single submitter
Method: clinical testing
Li-Fraumeni syndrome
Allele origin: germline
Invitae
Accession: SCV000166395.8
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces aspartic acid with histidine at codon 49 of the TP53 protein (p.Asp49His). The aspartic acid residue is highly conserved and there … (more)
Uncertain significance
(Jun 07, 2016)
criteria provided, single submitter
Method: clinical testing
Li-Fraumeni syndrome 1
Allele origin: unknown
Counsyl
Accession: SCV000488754.1
Submitted: (Nov 23, 2016)
Evidence details
Publications
PubMed (4)
Uncertain significance
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Li-Fraumeni syndrome 1
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001282023.1
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (2)
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Uncertain significance
(Aug 20, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000686722.3
Submitted: (May 19, 2020)
Comment:
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 … (more)
Evidence details
Uncertain significance
(Mar 14, 2019)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360862.1
Submitted: (Mar 06, 2020)
Evidence details
Publications
PubMed (3)
Comment:
Variant summary: TP53 c.145G>C (p.Asp49His) results in a non-conservative amino acid change located in the transactivation domain 2 of the encoded protein sequence. Four of … (more)
Uncertain significance
(May 01, 2019)
criteria provided, single submitter
Method: research
Hereditary breast and ovarian cancer syndrome
Allele origin: germline
Cancer Genomics Group,Japanese Foundation For Cancer Research
Accession: SCV001193756.2
Submitted: (Jun 25, 2020)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Prevalence of disease-causing genes in Japanese patients with <i>BRCA1/2</i>-wildtype hereditary breast and ovarian cancer syndrome. Kaneyasu T NPJ breast cancer 2020 PMID: 32566746
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Momozawa Y Nature communications 2018 PMID: 30287823
Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines. Ohmoto A Journal of gastroenterology 2018 PMID: 29667044
Nodular Lymphocyte-predominant Hodgkin Lymphoma in a 15-Year-Old Boy With Li-Fraumeni Syndrome Having a Germline TP53 D49H Mutation. Yamazaki F Journal of pediatric hematology/oncology 2018 PMID: 28902083
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Prevalence of low-penetrant germline TP53 D49H mutation in Japanese cancer patients. Yamaguchi K Biomedical research (Tokyo, Japan) 2016 PMID: 27545002
The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies. Rigacci S Biophysical journal 2008 PMID: 18199664
The interaction of p53 with replication protein A mediates suppression of homologous recombination. Romanova LY Oncogene 2004 PMID: 15489903
Mutant p53 in bone marrow stromal cells increases VEGF expression and supports leukemia cell growth. Narendran A Experimental hematology 2003 PMID: 12901974
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Kato S Proceedings of the National Academy of Sciences of the United States of America 2003 PMID: 12826609
Interaction between replication protein A and p53 is disrupted after UV damage in a DNA repair-dependent manner. Abramova NA Proceedings of the National Academy of Sciences of the United States of America 1997 PMID: 9207066
Loss of transactivation and transrepression function, and not RPA binding, alters growth suppression by p53. Leiter LM Oncogene 1996 PMID: 8700525
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3ae5f394-d710-4984-8d13-7c585ade67dc - - - -

Text-mined citations for rs587780728...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 24, 2021