NM_000546.6(TP53):c.1010G>A (p.Arg337His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: May 19, 2023
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:: RCV000128923.17

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:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172792	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 24, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11481490, 11753428, 16494995, 18248785, 19877175, 23570263, 24936644, 27714481, 28472496 Citation Link,
SCV000537678	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 16, 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
SCV002582334	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005407752	Molecular Diagnostics Laboratory, Catalan Institute of Oncology	criteria provided, single submitter (Fortuno et al. (Hum Mutat. 2021))	Pathogenic (May 19, 2023)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 12826609, 18940924, 10864200, 16933305, 18270399, 21630152, 21440489, 22619358, 28453760, 30147334, 11521785, 27101110, 29956451, 27601191, 32292755, 17940213, 18373486, 33300245

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	3	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma.

Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G, Cat I, Stratakis CA, Sandrini R.

Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9330-5.

PubMed [citation]

PMID:: 11481490
PMCID:: PMC55420

A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.

DiGiammarino EL, Lee AS, Cadwell C, Zhang W, Bothner B, Ribeiro RC, Zambetti G, Kriwacki RW.

Nat Struct Biol. 2002 Jan;9(1):12-6.

PubMed [citation]

PMID:: 11753428

See all PubMed Citations (38)

Details of each submission

From Ambry Genetics, SCV000172792.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.R337H pathogenic mutation (also known as c.1010G>A) is located in coding exon 9 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 1010. The arginine at codon 337 is replaced by histidine, an amino acid with highly similar properties. There currently exists a relatively extensive body of literature regarding this alteration. It has been detected at high frequency in Brazilian LFS families and is highly associated with a common haplotype, providing strong evidence of a founder effect in this population (Garritano et al. Hum Mutat. 2010 Feb;31(2):143-50). Ribeiro and colleagues described p.R337H as a low-penetrance mutation, primarily associated with adrenal cortical tumor risk in childhood; another study identified this mutation at a high (12.1%) frequency in Brazilian women with early-onset breast cancer (Ribeiro RC et al. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9330-5; Giacomazzi J et al, PLoS ONE 2014 ; 9(6):e99893). Other studies have led authors to conclude that the lifetime cancer risks for carriers of this mutation are similar to those of other LFS families, although p.R337H-associated cancers tend to occur with a later age of onset (Garritano et al. Hum Mutat. 2010 Feb;31(2):143-50). Families with this mutation have been reported with a wide spectrum of tumors including, but not limited to, breast cancers, brain cancers, soft tissue sarcomas, and adrenocortical carcinoma (Achatz et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Borges LM and Avres FM. Genet Mol Res. 2015 Dec 16;14(4):17034-43; IARC Database http://www-p53.iarc.fr/; Andrade RC et al. Fam. Cancer. 2017 Apr;16(2):243-248; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). One functional study demonstrated that the reduction in transcriptional activity and DNA binding resulting from this amino acid substitution is similar to that observed in null mutations (Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). In addition, this amino acid substitution occurs within the protein tetramerization domain and alters the ability of p53 to form stabilizing oligomers with high DNA-binding capacity in cells with elevated pH levels. This pH dependence may explain the incomplete penetrance observed in many families carrying the p.R337H mutation and has led to the hypothesis that p.R337H is a conditional mutant (DiGiammarino et al. Nat Struct Biol. 2002, 9:12-6; Giacomazzi J, et al. BMC Cancer 2013 Apr;13(1):187). Given the inter-familial variability in penetrance and tumor patterns described to date, some have suggested that surveillance recommendations for p.R337H carriers should be based on family cancer history (Palmero et al. Cancer Lett. 2008 Mar 8;261(1):21-5). Based on the available evidence, p.R337H is classified as a pathogenic mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000537678.4

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

From Genome-Nilou Lab, SCV002582334.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Diagnostics Laboratory, Catalan Institute of Oncology, SCV005407752.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

c.1010G>A, located in exon 10 of the TP53 gene, is predicted to result in the substitution of Arginine by Histidine at codon 337, p.(Arg337His). This variant is found in 1/236428 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. This variant has a BayesDel score 0.17 and Align GVGD (Zebrafish) is Class C0. Transactivation assays show a partially function allele according to Kato 2003 (PMID: 12826609) and there is a second assay showing low function (tetramer assay, PMID: 18940924) (PS3_Moderate). At least, this variant has been reported in 33 Chompret individuals, which awards 16 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 10864200, 16933305, 18270399, 21630152, 21440489, 22619358, 28453760, 30147334, among others) (PS4). It has been observed cosegregation (7 meiosis) in three families (PMID: 11521785, 27101110, 29956451) (PP1_Strong). In addition, this variant has been identified de novo in 4 individuals (PMID: 27601191, 27101110, 32292755) (PM6_Very Strong). The variant is present in >3 living unaffected individuals above 55 years of age (PMID: 17940213, 18373486) (BS4). This variant is a founder in Brasil. It has been reported in ClinVar (15x as pathogenic, 1x as likely pathogenic), LOVD (2x as pathogenic, 2x NA), CancerHotspots (4 somatic observations). Based on the currently available information, c.1010G>A is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.

#	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		not provided	not provided	3	not provided

Last Updated: Dec 14, 2024

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