NM_000546.6(TP53):c.1010G>A (p.Arg337His) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 19, 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:: RCV000197240.22

Allele description [Variation Report for NM_000546.6(TP53):c.1010G>A (p.Arg337His)]

NM_000546.6(TP53):c.1010G>A (p.Arg337His)

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.1010G>A (p.Arg337His)

HGVS:

NC_000017.11:g.7670699C>T
NG_017013.2:g.21852G>A
NM_000546.6:c.1010G>AMANE SELECT
NM_001126112.3:c.1010G>A
NM_001126113.3:c.*29G>A
NM_001126114.3:c.*117G>A
NM_001126115.2:c.614G>A
NM_001126116.2:c.*117G>A
NM_001126117.2:c.*29G>A
NM_001126118.2:c.893G>A
NM_001276695.3:c.*29G>A
NM_001276696.3:c.*117G>A
NM_001276697.3:c.533G>A
NM_001276698.3:c.*117G>A
NM_001276699.3:c.*29G>A
NM_001276760.3:c.893G>A
NM_001276761.3:c.893G>A
NP_000537.3:p.Arg337His
NP_000537.3:p.Arg337His
NP_001119584.1:p.Arg337His
NP_001119587.1:p.Arg205His
NP_001119590.1:p.Arg298His
NP_001263626.1:p.Arg178His
NP_001263689.1:p.Arg298His
NP_001263690.1:p.Arg298His
LRG_321t1:c.1010G>A
LRG_321:g.21852G>A
LRG_321p1:p.Arg337His
NC_000017.10:g.7574017C>T
NM_000546.4:c.1010G>A
NM_000546.5:c.1010G>A
P04637:p.Arg337His
p.R337H

Protein change:

R178H; ARG337HIS

Links:

UniProtKB: P04637#VAR_035016; OMIM: 191170.0035; dbSNP: rs121912664

NCBI 1000 Genomes Browser:

rs121912664

Molecular consequence:

NM_001126113.3:c.*29G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126114.3:c.*117G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126116.2:c.*117G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126117.2:c.*29G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276695.3:c.*29G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276696.3:c.*117G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276698.3:c.*117G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276699.3:c.*29G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000546.6:c.1010G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.1010G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.614G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.893G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.533G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.893G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.893G>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000253848	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10864200, 16033918, 16494995, 21192060, 23733769, 29979965, 30224644, 9704930, 12826609, 9704931, 20407015, 28492532
SCV001547487	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 6, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004823731	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 9582268, 10864200, 12826609, 16033918, 16494995, 19046423, 19717094, 20407015, 21192060, 22455664, 24936644, 27223487, 27663983, 27714481, 30224644, 25741868
SCV004847779	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 17, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27663983, 27223487, 19877175, 26681051, 27081505, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors.

Custódio G, Parise GA, Kiesel Filho N, Komechen H, Sabbaga CC, Rosati R, Grisa L, Parise IZ, Pianovski MA, Fiori CM, Ledesma JA, Barbosa JR, Figueiredo FR, Sade ER, Ibañez H, Arram SB, Stinghen ST, Mengarelli LR, Figueiredo MM, Carvalho DC, Avilla SG, Woiski TD, et al.

J Clin Oncol. 2013 Jul 10;31(20):2619-26. doi: 10.1200/JCO.2012.46.3711. Epub 2013 Jun 3.

PubMed [citation]

PMID:: 23733769
PMCID:: PMC3808236

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 (24)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000253848.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 337 of the TP53 protein (p.Arg337His). This variant is present in population databases (rs121912664, gnomAD 0.006%). This missense change has been observed in individual(s) with multiple types of cancer (PMID: 10864200, 16033918, 16494995, 21192060, 23733769). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12379). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) did not meet the statistical confidence thresholds required to predict the impact of this variant on TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 9704930, 12826609, 20407015). This variant disrupts the p.Arg337 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9704931, 20407015). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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 Cancer Variant Interpretation Group UK, Institute of Cancer Research, London, SCV001547487.1

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

Description

Data included in classification: Multiple case reports of this variant in the literature in cases meeting Chompret criteria, due to its identification in children with adrenocortical cancer. 117 reports on IARC database (germline). (PS4_Strong). Variant is absent from 56,697 NFE gnomAD controls (N.B. present in 2 latino controls and 1 other but known to be a founder mutation in the Brazilian population) (PM2_sup). Variant predicted as deleterious by BayesDel 0.178 and AlignGVGD C25 (PP3_sup) Data not included in classification: 2* classification of pathogenic on ClinVar, multiple submitters Kato et al, 2003: variant is partially functional on yeast based assay (PMID: 12826609). Giacomelli et al 2008 (PMID: 30224644) no dominant negative activity or loss of function shown on functional studies.

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

From All of Us Research Program, National Institutes of Health, SCV004823731.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (16)

Description

This missense variant replaces arginine with histidine at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the variant protein impacted protein stability and tetramerization, however, this defect may appear mild in some transactivation and growth inhibition assays (PMID: 9582268, 12826609, 20407015, 30224644; and IARC database). This variant is known to be a Brazilian founder mutation and observed in approximately 0.3% of the population in southern Brazil (PMID: 24936644, 27663983). This variant has been reported in numerous Brazilian individuals and families affected with Li-Fraumeni syndrome meeting Chompret criteria (PMID: 10864200, 16033918, 21192060, 27714481), Li-Fraumeni-like syndrome (PMID: 16494995), and early-onset breast cancer (PMID: 19046423, 22455664, 27223487). Studies of families carrying this variant have shown extremely variable cancer risk in individuals and identified several unaffected adult carriers, suggesting age-dependent (and possibly incomplete) penetrance of this variant (PMID: 19717094). This variant has been identified in 3/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon (p.Arg337Cys, p.Arg337Leu and p.Arg337Pro) have been reported as disease-causing in ClinVar (variation ID: 142536, 142828, 177879), suggesting that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Pathogenic.

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Arg337His variant in TP53 has been reported in numerous individuals with Li-Fraumeni syndrome and is thought to be a founder allele in Southern Brazil (Achatz 2016, Andrade 2016, Borges 2016). Although cancers associated with this allele tend to occur at a later age compared to other pathogenic variants in TP53, the lifetime risk seems to be similar to other LFS-associated TP53 variants (Garritano 2010). This variant has also been reported in ClinVar (Variation ID 12379). It has been identified in 0.007% (2/24544) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additional variants involving this codon (p.Arg337Cys, p.Arg337Leu) have been identified in individuals with cancer and are classified as likely pathogenic/pathogenic by clinical laboratories in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PM2, PS4, PP1_strong, PP3, PM5.

#	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

Last Updated: Nov 3, 2024

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