17-7670699-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PM1_Supporting PS3 PP3 PM5_Supporting PS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000546.6(TP53):c.1010G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 337 (p.Arg337Pro). This variant received a total of 0.5 points across 1 proband and therefore PS4 cannot be applied (PS4 not met; PMID:25584008). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with a moderately LFS-associated cancer totaling 1 phenotype point (PS2_Supporting; Internal contributor). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 3 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID:30311369) (PM1_Supporting). Computational predictor scores (BayesDel = 0.407328, Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (p.Arg337Leu) in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3, PS2_Supporting, PM1_Supporting, PM2_Supporting, PM5_Supporting. (Bayesian Points: 9; VCEP specifications version 2.3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000014/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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>C	p.Arg337Pro	missense	Exon 10 of 11	NP_000537.3
	TP53	NM_001126112.3		c.1010G>C	p.Arg337Pro	missense	Exon 10 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.1010G>C	p.Arg337Pro	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>C	p.Arg337Pro	missense	Exon 10 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.1010G>C	p.Arg337Pro	missense	Exon 10 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.893G>C	p.Arg298Pro	missense	Exon 9 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:3

May 07, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6(TP53):c.1010G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 337 (p.Arg337Pro). This variant received a total of 0.5 points across 1 proband and therefore PS4 cannot be applied (PS4 not met; PMID: 25584008). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with a moderately LFS-associated cancer totaling 1 phenotype point (PS2_Supporting; Internal contributor). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 3 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Computational predictor scores (BayesDel = 0.407328, Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (p.Arg337Leu) in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3, PS2_Supporting, PM1_Supporting, PM2_Supporting, PM5_Supporting. (Bayesian Points: 9; VCEP specifications version 2.3)

Aug 13, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 10864200, 16033918, 16494995, 21192060). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect TP53 protein function (PMID: 12826609, 19454241, 29955864). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 20426520). ClinVar contains an entry for this variant (Variation ID: 177879). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 337 of the TP53 protein (p.Arg337Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline.

Hereditary cancer-predisposing syndrome Pathogenic:3

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 28, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R337P variant (also known as c.1010G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1010. The arginine at codon 337 is replaced by proline, an amino acid with dissimilar properties. This alteration was identified in a 5 year old patient with acute lymphoblastic leukemia and adrenocortical carcinoma, as well as several family members with cancer (Karakas Z et al. Pediatr Hematol Oncol, 2010 May;27:297-305). This variant is in the oligomerization domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays, and loss of tetramer formation in studies conducted in human cell lines (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Fischer NW et al. J. Natl. Cancer Inst., 2018 12;110:1418-1421). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Jan 14, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with proline at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein to be defective in tetramer formation (PMID: 19454241, 20978130, 29955864) and transactivation function (PMID: 10519380, 10719737, 12826609, 19454241, 29955864). This variant has been reported in three individuals affected with Li-Fraumeni syndrome (PMID: 2042652, 29955864). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same amino acid position, p.Arg337His, is known to be disease-causing (ClinVar variation ID: 12379), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic.

Li-Fraumeni syndrome 1 Pathogenic:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	0.14
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.24
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.80		Loss of MoRF binding (P = 0.027)
MVP		0.99
MPC		0.45
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.99
gMVP		0.88
Mutation Taster		=1/99	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: COSV52828545; COSMIC: COSV52828545;