17-7670699-C-T

Variant names:

• chr17-7670699-C-T
• rs121912664
• NM_000546.6:c.1010G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.1010G>A​(p.Arg337His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,low penetrance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:29
• Conservation: PhyloP100: 0.244
• Publications: 602 publications found

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 21 benign, 28 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7670700-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 237938.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 17-7670699-C-T is Pathogenic according to our data. Variant chr17-7670699-C-T is described in ClinVar as Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance. ClinVar VariationId is 12379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.1010G>A	p.Arg337His	missense	Exon 10 of 11	NP_000537.3
	TP53	NM_001126112.3		c.1010G>A	p.Arg337His	missense	Exon 10 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.1010G>A	p.Arg337His	missense	Exon 11 of 12	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.1010G>A	p.Arg337His	missense	Exon 10 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.1010G>A	p.Arg337His	missense	Exon 10 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.893G>A	p.Arg298His	missense	Exon 9 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250846 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111942

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.000131 AC: 2 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000140 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance

Submissions summary: Pathogenic:29

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:6

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 09, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Feb 16, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Feb 14, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 14, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3, PS4, PP1

Apr 21, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PS3, PM2, PM5, PP3, PP5; Variant was found in heterozygous state.

Li-Fraumeni syndrome Pathogenic:5

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling incorporating data from in vitro 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.

May 01, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2020

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 17, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Pathogenic:4

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Oct 07, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Hereditary cancer-predisposing syndrome Pathogenic:4

Feb 18, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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.

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 19, 2023

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Adrenocortical carcinoma, hereditary Pathogenic:2

Dec 28, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A 4-year-old girl with metastatic adrenocortical carcinoma in the right kidney & multiple gallstones. The father also has this type of cancer.

Hereditary breast ovarian cancer syndrome Pathogenic:2

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Aug 12, 2025

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Pathogenic, low penetrance

Review Status: criteria provided, single submitter

Collection Method: curation

Known Brazilian founder Mutation with reduced penetrance for LFS. 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) 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;; This classification follows the ClinGen ENIGMA BRCA1 v1.1.0 classification scheme

Breast neoplasm Pathogenic:1

Clinical and Functional Genomics Group, A.C.Camargo Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Pathogenic:1

Mar 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ADRENOCORTICAL CARCINOMA, PEDIATRIC Pathogenic:1

Jan 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

TP53-related disorder Pathogenic:1

Oct 01, 2024

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Squamous cell carcinoma of the head and neck Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	0.0026
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.24
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.69
Sift	Benign	0.038	D
Sift4G	Benign	0.15	T
Polyphen		0.96	D
Vest4		0.71
MutPred		0.93		Loss of MoRF binding (P = 0.0485)
MVP		0.96
MPC		0.41
ClinPred		0.79	D
GERP RS		3.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.74
gMVP		0.57
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121912664; hg19: chr17-7574017; COSMIC: COSV52691988; COSMIC: COSV52691988;