NM_000546.6(TP53):c.145G>C (p.Asp49His) AND Li-Fraumeni syndrome 1

Germline classification:: Likely benign (4 submissions)
Last evaluated:: Jan 10, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000410497.11

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]

Condition(s)

Name:: Li-Fraumeni syndrome 1 (LFS)
Identifiers:: Gene: 553989; MedGen: C1835398; Orphanet: 524; OMIM: 151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000488754	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Jun 7, 2016)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18199664, 9207066, 8700525, 15489903 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001282023	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18199664, 27545002 Citation Link,
SCV001737934	ClinGen TP53 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen TP53 ACMG Specifications v1-2)	Likely benign (Jan 10, 2022)	germline	curation	Citation Link,
SCV004017878	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Apr 11, 2023)	unknown	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Interaction between replication protein A and p53 is disrupted after UV damage in a DNA repair-dependent manner.

Abramova NA, Russell J, Botchan M, Li R.

Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7186-91.

PubMed [citation]

PMID:: 9207066
PMCID:: PMC23787

Loss of transactivation and transrepression function, and not RPA binding, alters growth suppression by p53.

Leiter LM, Chen J, Marathe T, Tanaka M, Dutta A.

Oncogene. 1996 Jun 20;12(12):2661-8.

PubMed [citation]

PMID:: 8700525

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000488754.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001282023.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen TP53 Variant Curation Expert Panel, ClinGen, SCV001737934.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

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 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, TP53 c.125G>C (p.D49H) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4, BS2_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004017878.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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