NM_000546.6(TP53):c.974G>T (p.Gly325Val) AND Li-Fraumeni syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 1, 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:: RCV000232570.12

Allele description [Variation Report for NM_000546.6(TP53):c.974G>T (p.Gly325Val)]

NM_000546.6(TP53):c.974G>T (p.Gly325Val)

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.974G>T (p.Gly325Val)

HGVS:

NC_000017.11:g.7673554C>A
NG_017013.2:g.18997G>T
NM_000546.6:c.974G>TMANE SELECT
NM_001126112.3:c.974G>T
NM_001126113.3:c.974G>T
NM_001126114.3:c.974G>T
NM_001126115.2:c.578G>T
NM_001126116.2:c.578G>T
NM_001126117.2:c.578G>T
NM_001126118.2:c.857G>T
NM_001276695.3:c.857G>T
NM_001276696.3:c.857G>T
NM_001276697.3:c.497G>T
NM_001276698.3:c.497G>T
NM_001276699.3:c.497G>T
NM_001276760.3:c.857G>T
NM_001276761.3:c.857G>T
NP_000537.3:p.Gly325Val
NP_000537.3:p.Gly325Val
NP_001119584.1:p.Gly325Val
NP_001119585.1:p.Gly325Val
NP_001119586.1:p.Gly325Val
NP_001119587.1:p.Gly193Val
NP_001119588.1:p.Gly193Val
NP_001119589.1:p.Gly193Val
NP_001119590.1:p.Gly286Val
NP_001263624.1:p.Gly286Val
NP_001263625.1:p.Gly286Val
NP_001263626.1:p.Gly166Val
NP_001263627.1:p.Gly166Val
NP_001263628.1:p.Gly166Val
NP_001263689.1:p.Gly286Val
NP_001263690.1:p.Gly286Val
LRG_321t1:c.974G>T
LRG_321:g.18997G>T
LRG_321p1:p.Gly325Val
NC_000017.10:g.7576872C>A
NM_000546.4:c.974G>T
NM_000546.5:c.974G>T
P04637:p.Gly325Val
p.G325V

Protein change:

G166V; GLY325VAL

Links:

UniProtKB: P04637#VAR_006039; OMIM: 191170.0021; dbSNP: rs121912659

NCBI 1000 Genomes Browser:

rs121912659

Molecular consequence:

NM_000546.6:c.974G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.974G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.974G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.974G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.578G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.578G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.578G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.857G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.857G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.857G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.497G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.497G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.497G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.857G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.857G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

Recent activity

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Aquaporin-like superfamily protein [Arabidopsis thaliana]
Aquaporin-like superfamily protein [Arabidopsis thaliana]
gi|15219403|ref|NP_177462.1|

Protein
tonoplast intrinsic protein 4;1 [Arabidopsis thaliana]
tonoplast intrinsic protein 4;1 [Arabidopsis thaliana]
gi|15225195|ref|NP_180152.1|

Protein
cellular organisms 16S ribosomal RNA gene, partial sequence; 16S-23S ribosomal R...
cellular organisms 16S ribosomal RNA gene, partial sequence; 16S-23S ribosomal RNA intergenic spacer, complete sequence; and 23S ribosomal RNA gene, partial sequence.
PopSet: 219810417

PopSet
EVIDENCE ON PHYSICAL ACTIVITY AND SEDENTARY BEHAVIOUR FOR CHILDREN AND ADOLESCEN...
EVIDENCE ON PHYSICAL ACTIVITY AND SEDENTARY BEHAVIOUR FOR CHILDREN AND ADOLESCENTS (5 TO UNDER 18 YEARS OF AGE) - WHO Guidelines on Physical Activity and Sedentary Behaviour
Ankrd40 ankyrin repeat domain 40 [Rattus norvegicus]
Ankrd40 ankyrin repeat domain 40 [Rattus norvegicus]
Gene ID:690586

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000285218	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 1, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 1565144, 32191290, 29979965, 12826609, 16007150, 20128691, 21343334, 29955864, 30224644, 28492532
SCV004823740	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Nov 2, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 1565144, 10629033, 12826609, 16007150, 17606709, 20128691, 21343334, 29955864, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000285218

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 1, 2024)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004823740

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Nov 2, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.

Mirabello L, Zhu B, Koster R, Karlins E, Dean M, Yeager M, Gianferante M, Spector LG, Morton LM, Karyadi D, Robison LL, Armstrong GT, Bhatia S, Song L, Pankratz N, Pinheiro M, Gastier-Foster JM, Gorlick R, de Toledo SRC, Petrilli AS, Patino-Garcia A, Lecanda F, et al.

JAMA Oncol. 2020 May 1;6(5):724-734. doi: 10.1001/jamaoncol.2020.0197.

PubMed [citation]

PMID:: 32191290
PMCID:: PMC7082769

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, Hopf TA, Marks DS, Oren M, Segal E.

Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012. Erratum in: Mol Cell. 2018 Sep 6;71(5):873. doi: 10.1016/j.molcel.2018.08.013.

PubMed [citation]

PMID:: 29979965

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000285218.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 325 of the TP53 protein (p.Gly325Val). This variant is present in population databases (rs121912659, gnomAD 0.0009%). This missense change has been observed in individual(s) with colon carcinoma, Li-Fraumeni syndrome, non-Hodgkin lymphoma, and/or osteosarcoma (PMID: 1565144, 29955864, 32191290). ClinVar contains an entry for this variant (Variation ID: 12367). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 16007150, 20128691, 21343334, 29955864, 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.

#	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 All of Us Research Program, National Institutes of Health, SCV004823740.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (10)

Description

This missense variant replaces glycine with valine at codon 325 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). Experimental functional studies have shown this variant to behave as wild-type in transcriptional transactivation and human cell growth suppression assays (PMID: 12826609, 16007150, 17606709, 21343334, 29955864, 30224644, but has also shown moderate impact in DNA binding and apoptosis assays (PMID: 10629033, 20128691). This variant has been reported in an individual affected with non-Hodgkin lymphoma and colon cancer in the literature (PMID: 1565144). This variant has been identified in 1/251420 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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