VCV000012379.84 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(27)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 12379 Accession: VCV000012379.84

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7670699 (GRCh38) [ NCBI UCSC ] 17: 7574017 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 24, 2016	Dec 7, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.1010G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Arg337His	missense
NM_001126112.3:c.1010G>A	NP_001119584.1:p.Arg337His	missense
NM_001126113.3:c.*29G>A		3 prime UTR
NM_001126114.3:c.*117G>A		3 prime UTR
NM_001126115.2:c.614G>A	NP_001119587.1:p.Arg205His	missense
NM_001126116.2:c.*117G>A		3 prime UTR
NM_001126117.2:c.*29G>A		3 prime UTR
NM_001126118.2:c.893G>A	NP_001119590.1:p.Arg298His	missense
NM_001276695.3:c.*29G>A		3 prime UTR
NM_001276696.3:c.*117G>A		3 prime UTR
NM_001276697.3:c.533G>A	NP_001263626.1:p.Arg178His	missense
NM_001276698.3:c.*117G>A		3 prime UTR
NM_001276699.3:c.*29G>A		3 prime UTR
NM_001276760.3:c.893G>A	NP_001263689.1:p.Arg298His	missense
NM_001276761.3:c.893G>A	NP_001263690.1:p.Arg298His	missense
NC_000017.11:g.7670699C>T
NC_000017.10:g.7574017C>T
NG_017013.2:g.21852G>A
LRG_321:g.21852G>A
LRG_321t1:c.1010G>A	LRG_321p1:p.Arg337His
	P04637:p.Arg337His

... more HGVS ... less HGVS

Protein change

R337H, R205H, R298H, R178H

Other names

Canonical SPDI

NC_000017.11:7670698:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA000013 UniProtKB: P04637#VAR_035016 OMIM: 191170.0035 dbSNP: rs121912664 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TP53		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3373	3472

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Adrenocortical carcinoma, pediatric	Pathogenic (1)	no assertion criteria provided	Jan 1, 2006	RCV000013178.28
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Oct 7, 2022	RCV000481814.23
Adrenocortical carcinoma, hereditary	Pathogenic (2)	criteria provided, single submitter	Dec 28, 2023	RCV001375632.7
Li-Fraumeni syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 19, 2024	RCV000197240.22
Squamous cell carcinoma of the head and neck	Pathogenic (1)	criteria provided, single submitter	May 28, 2019	RCV000989700.4
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162248.3
Li-Fraumeni syndrome 1	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jun 18, 2022	RCV000576817.12
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 19, 2023	RCV000128923.17
Breast neoplasm	Pathogenic (1)	criteria provided, single submitter	-	RCV000413754.4
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2021	RCV002307364.4
Adrenocortical carcinoma, hereditary Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5 Bone osteosarcoma Carcinoma of pancreas Choroid plexus papilloma Colorectal cancer Familial cancer of breast Glioma susceptibility 1 Hepatocellular carcinoma Li-Fraumeni syndrome 1 Nasopharyngeal carcinoma	Pathogenic (1)	criteria provided, single submitter	Mar 25, 2022	RCV002496338.3
TP53-related disorder	Pathogenic (1)	no assertion criteria provided	Oct 1, 2024	RCV004797591.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (Silva et al. (BMC Med Genet. 2014)) Method: research	Breast Cancer Affected status: yes Allele origin: germline	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center Accession: SCV000492466.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Publications: PubMed (2) PubMed: 23469205‚ 24884479
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Squamous cell carcinoma of the head and neck Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140239.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Mar 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni Syndrome Affected status: yes Allele origin: germline	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London Accession: SCV001547487.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Geographic origin: United Kingdom
Pathogenic (Feb 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	DASA Accession: SCV002097308.1 First in ClinVar: Feb 20, 2022 Last updated: Feb 20, 2022	Publications: PubMed (9) PubMed: 28369373‚ 20407015‚ 20301488‚ 28387921‚ 28864397‚ 28984303‚ 28968711‚ 28756477‚ 30107858 Comment: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28369373; 20407015) - PS3. The … (more) Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28369373; 20407015) - PS3. The c.1010G>A;p.(Arg337His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12379; PMID: 20301488; 28387921; 28864397; 28984303; 28968711; 28756477; 30107858) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (P53_tetramer) - PM1. Pathogenic missense variant in this residue have been reported (ClinVar ID: 142536 - c.1009C>T;p.(Arg337Cys)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Genetics Program, Instituto Nacional de Cancer Accession: SCV002515183.1 First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022	Publications: PubMed (2) PubMed: 36329109‚ 12826609 Geographic origin: Brazil
Pathogenic (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000253848.13 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 28492532‚ 10864200‚ 16033918‚ 16494995‚ 21192060‚ 23733769‚ 12826609‚ 29979965‚ 30224644‚ 9704930‚ 20407015‚ 9704931 Comment: 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). … (more) 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. (less)
Pathogenic (May 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000537678.4 First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024	Publications: PubMed (15) PubMed: 9582268‚ 10864200‚ 12826609‚ 16033918‚ 16494995‚ 19046423‚ 19717094‚ 20407015‚ 21192060‚ 22455664‚ 24936644‚ 27223487‚ 27663983‚ 27714481‚ 30224644 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 17, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847779.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (5) PubMed: 27663983‚ 27223487‚ 19877175‚ 26681051‚ 27081505 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762195.1 First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021	Clinical Features: Neoplasm of the adrenal cortex (present) Sex: female
Pathogenic (Feb 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: maternal	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV002030174.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Likely pathogenic (Jun 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002582334.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Likely pathogenic (Jun 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002582996.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Pathogenic (Feb 16, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000677744.2 First in ClinVar: Jan 07, 2018 Last updated: Dec 24, 2022	Publications: PubMed (12) PubMed: 21192060‚ 12826609‚ 27223487‚ 16033918‚ 26452166‚ 27663983‚ 26681051‚ 10864200‚ 19717094‚ 11753428‚ 16494995‚ 26572807
Pathogenic (Mar 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Colorectal cancer Hepatocellular carcinoma Glioma susceptibility 1 Li-Fraumeni syndrome 1 Adrenocortical carcinoma, hereditary Bone osteosarcoma Familial pancreatic carcinoma Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002811422.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Sep 29, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568754.7 First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023	Comment: Founder variant present in 0.2-0.3% of the South Brazilian population (Garritano et al., 2010); Reported to result in lower cancer risks by early adulthood than … (more) Founder variant present in 0.2-0.3% of the South Brazilian population (Garritano et al., 2010); Reported to result in lower cancer risks by early adulthood than variants associated with classic Li-Fraumeni syndrome, with a 21% risk of cancer reported by age 45 per one study, but comparable lifetime cancer risks (Garritano et al., 2010; Mastellaro et al., 2017); Published functional studies demonstrate a damaging effect: reduced ability to form tetramers resulting in reduced transactivation in a pH-dependent manner, increased tumorigenesis in a knock-in mouse model (DiGiammarino et al., 2002; Jordan et al., 2010; Park et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19717094, 10864200, 15121773, 23794094, 11753428, 28369373, 27866339, 30588330, 29039119, 30535581, 32592449, 31978118, 21343334, 11481490, 12826609, 21192060, 18248785, 22170717, 22455664, 16033918, 23259501, 23733769, 21445348, 9704930, 11600572, 25736369, 21468523, 19046423, 22004116, 23570263, 16750598, 24784157, 23056559, 24936644, 26452166, 19877175, 27223487, 27275664, 26656232, 27663983, 28387921, 27081505, 25945745, 26823150, 28114597, 28254861, 16494995, 28968711, 28152038, 28864397, 28724667, 28472496, 30774760, 27714481, 30596752, 29392648, 29928384, 30042151, 30107858, 31748977, 29625052, 32039725, 32671623, 33603772, 30224644, 32485079, 31744167, 31889631, 33138793, 31778928, 26681051, 31105275, 31494577, 20407015, 15510160, 33258288, 33637564, 32986223, 32817165, 29922827, 30982232, 32156018) (less)
Pathogenic (Oct 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV004183390.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: ACMG classification criteria: PS3, PS4, PP1 Geographic origin: Brazil
Pathogenic (Oct 07, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004221343.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (68): PubMed: 34885220 35367578 36003761 30042151 30107858 28984303 28864397 28756477 28968711 28387921 28369373 27714481 27223487 26452166 24936644 24884479 23733769 23570263 23469205 21192060 20407015 19877175 19717094 18248785 16494995 16033918 15741269 15121773 12826609 11753428 11600572 11481490 10864200 9704930 33300245 23056559 29392648 21468523 25736369 33637564 29922827 30596752 31494577 23794094 32817165 25945745 27081505 32671623 22004116 32039725 21445348 31744167 32156018 32986223 19046423 16750598 21343334 28724667 30982232 31105275 31748977 31978118 32592449 33258288 33603772 9582268 30224644 22455664 Comment: The frequency of this variant in the general population, 0.000012 (3/250846 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.000012 (3/250846 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a Brazilian founder mutation associated with reduced penetrance, carrying a lower cancer risk than other TP53 pathogenic variants (PMID: 33300245 (2021), 31744167 (2019), 19877175 (2009)). It has been reported in up to 0.2 to 0.3% of the Brazilian population (PMID: 32592449 (2049), 19717094 (2009)). This variant has been seen in individuals with breast cancer (PMID: 32986223 (2021), 32039725 (2020), 30596752 (2018), 22455664 (2012)), Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 30107858 (2018), 29392648 (2018), 28756477 (2018), 21192060 (2011)), and children with adrenocortical tumors (ACT) (PMID: 32156018 (2020), 31744167 (2019), 16033918 (2006), 16033918 (2006), 15121773 (2004), 11481490 (2001)). Some published functional studies are conflicting, but the majority have found that this variant causes a partial or conditional damaging effect on TP53 function (PMID: 35367578 (2022), 33637564 (2021), 30042151 (2018), 28369373 (2017), 23056559 (2012), 21343334 (2011), 20407015 (2010), 12826609 (2003), 11753428 (2002), 9704930 (1998)). Based on the available information, this variant is classified as a pathogenic variant with reduced penetrance. (less)
Pathogenic (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004823731.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (15) PubMed: 9582268‚ 10864200‚ 12826609‚ 16033918‚ 16494995‚ 19046423‚ 19717094‚ 20407015‚ 21192060‚ 22455664‚ 24936644‚ 27223487‚ 27663983‚ 27714481‚ 30224644 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Zygosity: Single Heterozygote
Pathogenic (Jan 24, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000172792.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (9) PubMed: 11481490‚ 11753428‚ 16494995‚ 18248785‚ 19877175‚ 23570263‚ 24936644‚ 27714481‚ 28472496 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adrenocortical carcinoma, hereditary Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206232.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Apr 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382098.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: ACMG Criteria: PS3, PM2, PM5, PP3, PP5; Variant was found in heterozygous state. Clinical Features: Adrenal cortex carcinoma (present) , Right ventricular cardiomyopathy (present)
Pathogenic (May 19, 2023)	criteria provided, single submitter (Fortuno et al. (Hum Mutat. 2021)) Method: clinical testing	Hereditary cancer-predisposing syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Molecular Diagnostics Laboratory, Catalan Institute of Oncology Accession: SCV005407752.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (17) PubMed: 12826609‚ 18940924‚ 10864200‚ 16933305‚ 18270399‚ 21630152‚ 21440489‚ 22619358‚ 28453760‚ 30147334‚ 11521785‚ 27101110‚ 29956451‚ 27601191‚ 32292755‚ 17940213‚ 18373486 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 01, 2006)	no assertion criteria provided Method: literature only	ADRENOCORTICAL CARCINOMA, PEDIATRIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033425.3 First in ClinVar: Apr 04, 2013 Last updated: Feb 01, 2018	Publications: PubMed (6) PubMed: 11481490‚ 11753428‚ 11600572‚ 15121773‚ 16033918‚ 15741269 Comment on evidence: The incidence of pediatric adrenocortical carcinoma (202300) in southern Brazil is 10 to 15 times higher than that of pediatric ADCC worldwide. Because childhood ADCC … (more) The incidence of pediatric adrenocortical carcinoma (202300) in southern Brazil is 10 to 15 times higher than that of pediatric ADCC worldwide. Because childhood ADCC is associated with Li-Fraumeni syndrome (151623), Ribeiro et al. (2001) examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germline point mutation in exon 10 of the p53 gene, a G-to-A transition at nucleotide 1010 encoding an arg337-to-his (R337H) amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating the possibility of a founder effect. In tumor cells, the wildtype allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ADCC. DiGiammarino et al. (2002) demonstrated that the mutant tetramerization domain of p53 harboring the R337H mutation adopts a native-like fold but is less stable than the wildtype domain. Furthermore, the stability of the p53 R337H-bearing tetramer is highly sensitive to pH in the physiologic range; this sensitivity correlates with the protonation state of the mutated his337. DiGiammarino et al. (2002) concluded that their results demonstrated a pH-sensitive molecular defect of p53, suggesting that the pH-dependent p53 dysfunction is the molecular basis for these cases of ADCC in Brazilian children. Latronico et al. (2001) studied this mutation in a larger series of 55 patients (37 adults and 18 children) with benign and malignant sporadic adrenocortical tumors. None of the patients had family cancer histories that conformed to the criteria for Li-Fraumeni syndrome. Among the 19 patients with the R337H mutation, only 1 boy and 3 adults showed fatal evolution or recurrent metastases. This mutation was also identified in heterozygous state in asymptomatic first-degree relatives of the patients, indicating that R337H mutation was inherited in most cases. The authors concluded that the germline R337H mutation of p53 protein is present at a high frequency (approximately 78%) in children with benign or malignant sporadic adrenocortical tumors, but it is not restricted to the pediatric group, since about 14% of adults with adrenocortical tumors also had this mutation. The presence of this mutation was related to unfavorable prognosis in most of the adults but not in the children with adrenocortical tumors. Longui et al. (2004) investigated the inhibin-alpha (INHA; 147380) gene in 46 Brazilian children with ADCC, 39 of whom were heterozygous carriers of R337H. Six patients were heterozygous for 3 INHA mutations, and Longui et al. (2004) concluded that INHA may be one of the contributing factors needed for adrenocortical tumor formation in pediatric patients with the R337H TP53 mutation. Figueiredo et al. (2006) identified the R337H mutation in 40 children from southern Brazil with ADCC. The mutation was also identified in 34.5% of relatives tested in parental carrier lines. The penetrance of ADCC among carriers of R337H was estimated at 9.9%. Pinto et al. (2005) studied deletion mapping of chromosome 17 in 30 adrenocortical tumors from 29 Brazilian patients (15 children and 14 adults). Sixteen patients had the germline R337H mutation. Loss of heterozygosity (LOH) analysis using 6 polymorphic microsatellite markers disclosed loss of the entire chromosome 17 in 18 tumors (10 adenomas and 8 carcinomas) from 17 patients. The R337H mutation was present in 13 of them. The authors demonstrated a high frequency of biallelic inactivation of p53 derived from 2 distinct events occurs, the germline R337H mutation and the acquired loss of the entire chromosome 17. The isolated loss of the entire chromosome 17 did not correlate with aggressive tumor behavior in these patients with adrenocortical tumors. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000692060.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Pathogenic (Apr 27, 2021)	no assertion criteria provided Method: clinical testing	Adrenocortical carcinoma, hereditary (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genome-Nilou Lab Accession: SCV001572529.1 First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021	Comment: A 4-year-old girl with metastatic adrenocortical carcinoma in the right kidney & multiple gallstones. The father also has this type of cancer. Clinical Features: Cholelithiasis (present) Zygosity: Single Heterozygote Age: 0-9 years Sex: female Ethnicity/Population group: Persian Geographic origin: Iran
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758162.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
Pathogenic (Oct 01, 2024)	no assertion criteria provided Method: clinical testing	TP53-related disorder Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV005419170.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024	Publications: PubMed (1) PubMed: 33300245
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Comment:

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.

Comment:

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28369373; 20407015) - PS3. The c.1010G>A;p.(Arg337His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12379; PMID: 20301488; 28387921; 28864397; 28984303; 28968711; 28756477; 30107858) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (P53_tetramer) - PM1. Pathogenic missense variant in this residue have been reported (ClinVar ID: 142536 - c.1009C>T;p.(Arg337Cys)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

Founder variant present in 0.2-0.3% of the South Brazilian population (Garritano et al., 2010); Reported to result in lower cancer risks by early adulthood than variants associated with classic Li-Fraumeni syndrome, with a 21% risk of cancer reported by age 45 per one study, but comparable lifetime cancer risks (Garritano et al., 2010; Mastellaro et al., 2017); Published functional studies demonstrate a damaging effect: reduced ability to form tetramers resulting in reduced transactivation in a pH-dependent manner, increased tumorigenesis in a knock-in mouse model (DiGiammarino et al., 2002; Jordan et al., 2010; Park et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19717094, 10864200, 15121773, 23794094, 11753428, 28369373, 27866339, 30588330, 29039119, 30535581, 32592449, 31978118, 21343334, 11481490, 12826609, 21192060, 18248785, 22170717, 22455664, 16033918, 23259501, 23733769, 21445348, 9704930, 11600572, 25736369, 21468523, 19046423, 22004116, 23570263, 16750598, 24784157, 23056559, 24936644, 26452166, 19877175, 27223487, 27275664, 26656232, 27663983, 28387921, 27081505, 25945745, 26823150, 28114597, 28254861, 16494995, 28968711, 28152038, 28864397, 28724667, 28472496, 30774760, 27714481, 30596752, 29392648, 29928384, 30042151, 30107858, 31748977, 29625052, 32039725, 32671623, 33603772, 30224644, 32485079, 31744167, 31889631, 33138793, 31778928, 26681051, 31105275, 31494577, 20407015, 15510160, 33258288, 33637564, 32986223, 32817165, 29922827, 30982232, 32156018)

Comment:

The frequency of this variant in the general population, 0.000012 (3/250846 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a Brazilian founder mutation associated with reduced penetrance, carrying a lower cancer risk than other TP53 pathogenic variants (PMID: 33300245 (2021), 31744167 (2019), 19877175 (2009)). It has been reported in up to 0.2 to 0.3% of the Brazilian population (PMID: 32592449 (2049), 19717094 (2009)). This variant has been seen in individuals with breast cancer (PMID: 32986223 (2021), 32039725 (2020), 30596752 (2018), 22455664 (2012)), Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 30107858 (2018), 29392648 (2018), 28756477 (2018), 21192060 (2011)), and children with adrenocortical tumors (ACT) (PMID: 32156018 (2020), 31744167 (2019), 16033918 (2006), 16033918 (2006), 15121773 (2004), 11481490 (2001)). Some published functional studies are conflicting, but the majority have found that this variant causes a partial or conditional damaging effect on TP53 function (PMID: 35367578 (2022), 33637564 (2021), 30042151 (2018), 28369373 (2017), 23056559 (2012), 21343334 (2011), 20407015 (2010), 12826609 (2003), 11753428 (2002), 9704930 (1998)). Based on the available information, this variant is classified as a pathogenic variant with reduced penetrance.

Comment:

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.

Comment:

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.

Germline Functional Evidence

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Li-Fraumeni Syndrome.	Adam MP	-	2024	PMID: 20301488
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service.	Matta BP	Scientific reports	2022	PMID: 36329109
Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer.	Megid TBC	Frontiers in oncology	2022	PMID: 36003761
p53 mutants G245S and R337H associated with the Li-Fraumeni syndrome regulate distinct metabolic pathways.	Meneghetti BV	Biochimie	2022	PMID: 35367578
Newborn Screening for the Detection of the TP53 R337H Variant and Surveillance for Early Diagnosis of Pediatric Adrenocortical Tumors: Lessons Learned and Way Forward.	Tosin KCF	Cancers	2021	PMID: 34885220
The Common Germline TP53-R337H Mutation Is Hypomorphic and Confers Incomplete Penetrance and Late Tumor Onset in a Mouse Model.	Jeffers JR	Cancer research	2021	PMID: 33637564
Prevalence of the Brazilian TP53 Founder c.1010G>A (p.Arg337His) in Lung Adenocarcinoma: Is Genotyping Warranted in All Brazilian Patients?	Vieira IA	Frontiers in genetics	2021	PMID: 33603772
Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.	Fortuno C	Human mutation	2021	PMID: 33300245
Germline variants of Brazilian women with breast cancer and detection of a novel pathogenic ATM deletion in early-onset breast cancer.	Bandeira G	Breast cancer (Tokyo, Japan)	2021	PMID: 32986223
Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.	Quaio CRDC	American journal of medical genetics. Part C, Seminars in medical genetics	2020	PMID: 33258288
A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome.	Gao F	Genome research	2020	PMID: 32817165
Frequency of the TP53 p.R337H mutation in a Brazilian cohort of pediatric patients with solid tumors.	Feitosa JADS	Molecular biology reports	2020	PMID: 32671623
TP53 p.Arg337His geographic distribution correlates with adrenocortical tumor occurrence.	Seidinger AL	Molecular genetics & genomic medicine	2020	PMID: 32592449
Acidic-Treated Acorn Pollen as Health Functional Food Materials for Improvement of Post-Menopausal Glucose Metabolism.	Nam SJ	Preventive nutrition and food science	2020	PMID: 32292755
High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53.	Brondani VB	Cancers	2020	PMID: 32156018
Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population.	da Costa E Silva Carvalho S	BMC medical genomics	2020	PMID: 32039725
The Brazilian TP53 mutation (R337H) and sarcomas.	Volc SM	PloS one	2020	PMID: 31978118
Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome).	Petry V	Familial cancer	2020	PMID: 31748977
High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers.	González-Acosta M	Journal of medical genetics	2020	PMID: 31494577
Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil.	Costa TEJ	Cancers	2019	PMID: 31744167
Genotype-phenotype associations among panel-based TP53+ subjects.	Rana HQ	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31105275
Germline mutation landscape of Chinese patients with familial breast/ovarian cancer in a panel of 22 susceptibility genes.	Wang J	Cancer medicine	2019	PMID: 30982232
TP53 p.Arg337His germline mutation prevalence in Southern Brazil: Further evidence for mutation testing in young breast cancer patients.	Hahn EC	PloS one	2018	PMID: 30596752
Mutational processes shape the landscape of TP53 mutations in human cancer.	Giacomelli AO	Nature genetics	2018	PMID: 30224644
Adenosquamous carcinoma of the lung.	Li C	OncoTargets and therapy	2018	PMID: 30147334
Whole-body magnetic resonance imaging of Li-Fraumeni syndrome patients: observations from a two rounds screening of Brazilian patients.	Paixão D	Cancer imaging : the official publication of the International Cancer Imaging Society	2018	PMID: 30107858
Mouse Homolog of the Human TP53 R337H Mutation Reveals Its Role in Tumorigenesis.	Park JH	Cancer research	2018	PMID: 30042151
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.	Kotler E	Molecular cell	2018	PMID: 29979965
The family of 14-3-3 proteins and specifically 14-3-3σ are up-regulated during the development of renal pathologies.	Rizou M	Journal of cellular and molecular medicine	2018	PMID: 29956451
Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.	Hu C	JAMA	2018	PMID: 29922827
The first two confirmed sub-Saharan African families with germline TP53 mutations causing Li-Fraumeni syndrome.	Macaulay S	Familial cancer	2018	PMID: 29392648
Analysis of clinically relevant somatic mutations in high-risk head and neck cutaneous squamous cell carcinoma.	Zilberg C	Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc	2018	PMID: 28984303
Adrenocortical tumors associated with the TP53 p.R337H germline mutation can be identified during child-care consultations.	Mastellaro MJ	Jornal de pediatria	2018	PMID: 28864397
p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers.	Macedo GS	Familial cancer	2018	PMID: 28756477
Spectrum of germline mutations in smokers and non-smokers in Brazilian non-small-cell lung cancer (NSCLC) patients.	Couto PP	Carcinogenesis	2017	PMID: 28968711
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage.	Zerdoumi Y	Human molecular genetics	2017	PMID: 28472496
Long-term Inflammation Transforms Intestinal Epithelial Cells of Colonic Organoids.	Hibiya S	Journal of Crohn's & colitis	2017	PMID: 28453760
Contribution of the TP53 R337H mutation to the cancer burden in southern Brazil: Insights from the study of 55 families of children with adrenocortical tumors.	Mastellaro MJ	Cancer	2017	PMID: 28387921
Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage.	Zerdoumi Y	Human molecular genetics	2017	PMID: 28369373
TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes.	Andrade RC	Familial cancer	2017	PMID: 27714481
The Inherited p53 Mutation in the Brazilian Population.	Achatz MI	Cold Spring Harbor perspectives in medicine	2016	PMID: 27663983
Quantum optical signatures in strong-field laser physics: Infrared photon counting in high-order-harmonic generation.	Gonoskov IA	Scientific reports	2016	PMID: 27601191
Early-onset breast cancer patients in the South and Southeast of Brazil should be tested for the TP53 p.R337H mutation.	Andrade KC	Genetics and molecular biology	2016	PMID: 27223487
In Reply.	Landon MB	Obstetrics and gynecology	2016	PMID: 27101110
Tetramer formation of tumor suppressor protein p53: Structure, function, and applications.	Kamada R	Biopolymers	2016	PMID: 26572807
R337H mutation of the TP53 gene as a clinical marker in cancer patients: a systematic review of literature.	Borges LM	Genetics and molecular research : GMR	2015	PMID: 26681051
Occurrence of Neuroblastoma among TP53 p.R337H Carriers.	Seidinger AL	PloS one	2015	PMID: 26452166
DNA methylation patterns of candidate genes regulated by thymine DNA glycosylase in patients with TP53 germline mutations.	Fortes FP	Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas	2015	PMID: 25945745
Prevalence of an inherited cancer predisposition syndrome associated with the germ line TP53 R337H mutation in Paraguay.	Legal EF	Cancer epidemiology	2015	PMID: 25736369
Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population.	Felix GE	Human genome variation	2014	PMID: 27081505
Prevalence of the TP53 p.R337H mutation in breast cancer patients in Brazil.	Giacomazzi J	PloS one	2014	PMID: 24936644
Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients.	Silva FC	BMC medical genetics	2014	PMID: 24884479
A TP53 founder mutation, p.R337H, is associated with phyllodes breast tumors in Brazil.	Giacomazzi J	Virchows Archiv : an international journal of pathology	2013	PMID: 23794094
Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors.	Custódio G	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2013	PMID: 23733769
TP53 p.R337H is a conditional cancer-predisposing mutation: further evidence from a homozygous patient.	Giacomazzi J	BMC cancer	2013	PMID: 23570263
Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.	Carraro DM	PloS one	2013	PMID: 23469205
Increased oxidative damage in carriers of the germline TP53 p.R337H mutation.	Macedo GS	PloS one	2012	PMID: 23056559
Knockdown of the adipokinetic hormone receptor increases feeding frequency in the two-spotted cricket Gryllus bimaculatus.	Konuma T	Endocrinology	2012	PMID: 22619358
The R337H mutation in TP53 and breast cancer in Brazil.	Gomes MC	Hereditary cancer in clinical practice	2012	PMID: 22455664
TP53 mutation p.R337H in gastric cancer tissues of a 12-year-old male child: evidence for chimerism involving a common mutant founder haplotype: case report.	da Silva EM	BMC cancer	2011	PMID: 22004116
Anaphase-promoting complex control in female mouse meiosis.	Jones KT	Results and problems in cell differentiation	2011	PMID: 21630152
Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor.	Lima Lde O	Arquivos brasileiros de endocrinologia e metabologia	2011	PMID: 21468523
Increased incidence of choroid plexus carcinoma due to the germline TP53 R337H mutation in southern Brazil.	Custodio G	PloS one	2011	PMID: 21445348
Expression and prognostic impact of indoleamine 2,3-dioxygenase in oral squamous cell carcinomas.	Laimer K	Oral oncology	2011	PMID: 21440489
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.	Monti P	Molecular cancer research : MCR	2011	PMID: 21343334
Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil.	Seidinger AL	Cancer	2011	PMID: 21192060
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.	Jordan JJ	Molecular cancer research : MCR	2010	PMID: 20407015
Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect.	Garritano S	Human mutation	2010	PMID: 19877175
Highly prevalent TP53 mutation predisposing to many cancers in the Brazilian population: a case for newborn screening?	Achatz MI	The Lancet. Oncology	2009	PMID: 19717094
Association of the germline TP53 R337H mutation with breast cancer in southern Brazil.	Assumpção JG	BMC cancer	2008	PMID: 19046423
Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand.	Gordo S	Proceedings of the National Academy of Sciences of the United States of America	2008	PMID: 18940924
Single-dose application of CNTF and BDNF improves remyelination of regenerating nerve fibers after C7 ventral root avulsion and replantation.	Lang EM	Journal of neurotrauma	2008	PMID: 18373486
Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil.	Palmero EI	Cancer letters	2008	PMID: 18248785
Cardiotrophin-1 is expressed in adipose tissue and upregulated in the metabolic syndrome.	Natal C	American journal of physiology. Endocrinology and metabolism	2008	PMID: 17940213
External hypofractionated whole-breast radiotherapy: now where does accelerated partial breast irradiation stand?	Munshi A	Journal of cancer research and therapeutics	2007	PMID: 18270399
Germline TP53 R337H mutation is not sufficient to establish Li-Fraumeni or Li-Fraumeni-like syndrome.	Ribeiro RC	Cancer letters	2007	PMID: 16750598
The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families.	Achatz MI	Cancer letters	2007	PMID: 16494995
Chick embryos exposed to trichloroethylene in an ex ovo culture model show selective defects in early endocardial cushion tissue formation.	Mishima N	Birth defects research. Part A, Clinical and molecular teratology	2006	PMID: 16933305
Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation.	Figueiredo BC	Journal of medical genetics	2006	PMID: 16033918
Deletion mapping of chromosome 17 in benign and malignant adrenocortical tumors associated with the Arg337His mutation of the p53 tumor suppressor protein.	Pinto EM	The Journal of clinical endocrinology and metabolism	2005	PMID: 15741269
Inhibin alpha-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers.	Longui CA	Journal of medical genetics	2004	PMID: 15121773
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
A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.	DiGiammarino EL	Nature structural biology	2002	PMID: 11753428
An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors.	Latronico AC	The Journal of clinical endocrinology and metabolism	2001	PMID: 11600572
A randomized trial of four cycles of adjuvant AC (adriamycin + cyclophosphamide) +/- two cycles of EP (etoposide + cisplatin) in node positive patients with breast cancer.	Içli F	Annals of oncology : official journal of the European Society for Medical Oncology	2001	PMID: 11521785
An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma.	Ribeiro RC	Proceedings of the National Academy of Sciences of the United States of America	2001	PMID: 11481490
P53 germline mutations in childhood cancers and cancer risk for carrier individuals.	Chompret A	British journal of cancer	2000	PMID: 10864200
Characterization of the oligomerization defects of two p53 mutants found in families with Li-Fraumeni and Li-Fraumeni-like syndrome.	Davison TS	Oncogene	1998	PMID: 9704931
Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni like family members.	Lomax ME	Oncogene	1998	PMID: 9704930
Nine hydrophobic side chains are key determinants of the thermodynamic stability and oligomerization status of tumour suppressor p53 tetramerization domain.	Mateu MG	The EMBO journal	1998	PMID: 9582268
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Text-mined citations for rs121912664 ...

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Record last updated Dec 15, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912664 ...