17-7670709-C-G

Variant names:

• chr17-7670709-C-G
• rs730882028
• NM_000546.6:c.1000G>C

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 7P and 8B. PM2_Supporting BS3 PS4 BS2 PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.1000G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 334 (p.Gly334Arg). This variant has been reported in 11 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 23580068, 25584008, 32675277, Internal lab contributors: SCV000216886.6, SCV000545272.7). The variant has been reported to segregate with LFS-associated cancers in 5 meioses in 3 families (PP1_Moderate; PMIDs: 32675277, Internal contributor). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributors: SCV000545272.9). This variant has an allele frequency of 0.000002543 (3/1179822 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been reported as a putative low penetrance founder variant in the Ashkenazi Jewish population (PMID:32675277). At this time, the TP53 VCEP cannot curate variants for low-penetrance designation. In summary, this variant is classified as a variant of unknown significance for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PS4, PP1_Moderate, PM2_supporting. (Bayesian Points: -1; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000007/MONDO:0018875/009

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:5
• Conservation: PhyloP100: 6.94
• Publications: 88 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: Uncertain_significance. The variant received -1 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.1000G>C	p.Gly334Arg	missense_variant	Exon 10 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1000G>C	p.Gly334Arg	missense_variant	Exon 10 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250586 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461528 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727038

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111798

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000233207), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5 Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2 Uncertain:1

Aug 05, 2024

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.1000G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 334 (p.Gly334Arg). This variant has been reported in 11 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 23580068, 25584008, 32675277, Internal lab contributors: SCV000216886.6, SCV000545272.7). The variant has been reported to segregate with LFS-associated cancers in 5 meioses in 3 families (PP1_Moderate; PMIDs: 32675277, Internal contributor). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; Internal lab contributors: SCV000545272.9). This variant has an allele frequency of 0.000002543 (3/1179822 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been reported as a putative low penetrance founder variant in the Ashkenazi Jewish population (PMID:32675277). At this time, the TP53 VCEP cannot curate variants for low-penetrance designation. In summary, this variant is classified as a variant of unknown significance for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PS4, PP1_Moderate, PM2_supporting. (Bayesian Points: -1; VCEP specifications version 2.0; 7/24/2024) -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 334 of the TP53 protein (p.Gly334Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome, including adrenocortical tumors, breast cancer, and hematological malignancies. However, this variant has also been observed in unaffected individuals, which is suggestive of reduced penetrance (PMID: 23580068, 24448499, 25452441, 25503501, 25584008, 32675277; internal data). ClinVar contains an entry for this variant (Variation ID: 182969). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 25584008, 29955864, 30224644). 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. -

Nov 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.1000G>C (p.Gly334Arg) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251700 control chromosomes. c.1000G>C has been reported in the literature in multiple individuals affected with features of Li-Fraumeni Syndrome and/or meeting the well-established Chrompet criteria used to diagnose Li-Fraumeni Syndrome (example, Wasserman_2015, Rath_2013, Powers_2020, Internal data). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. Experimental studies (transcriptional transactivation and colony suppression assays) show that this missense change does not affect the activity of TP53 (example, Wasserman_2015, Powers_2020, Fischer_2018). In summary, it has been reported predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance Li Fraumeni Syndrome (example, Powers_2020). The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 25452441, 27895058, 16818505, 29955864, 11782540, 22915647, 26230955, 21519010, 20407015, 27463065, 24448499, 25503501, 30327374, 17606709, 21343334, 26585234, NCCN_AML, NCCN_MDS, NCCN_MPN, 25952993, 27276561, 32675277, 23580068, 22186996, 27680515, 25584008, 27959731). ClinVar contains an entry for this variant (Variation ID: 182969). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 29, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G334R variant (also known as c.1000G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1000. The glycine at codon 334 is replaced by arginine, an amino acid with dissimilar properties. Residue G334 is the hinge residue between the &alpha;-helix and &beta;-sheet in the tetramerization domain of the p53 protein (Clore et al. Nat Struct Biol. 1995 Apr;2(4):321-33) and has been shown to be sensitive to substitution through in vitro analysis and predictive modeling (Kawaguchi et al. Oncogene. 2005 Oct 20;24(46):6976-81; Higa et al. Genet Mol Biol. 2009 Jul;32(3):626-33). This alteration has been detected in multiple patients with childhood onset adrenal cortical carcinoma (ACC), primarily of Ashkenazi Jewish descent, (Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9; Ambry internal data), and an individual with triple positive breast cancer who met Chompret criteria for Li-Fraumeni Syndrome (Rath et al. Breast Cancer Res. Treat. 2013 May;139(1):193-8). Functional studies conducted in yeast and human cell lines have shown this variant is able to form tetramers, and has transactivation capacity and colony reduction activity similar to wild type (Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9; Giacomelli AO et al. Nat. Genet. 2018 10;50:1381-1387; Fischer NW et al. J. Natl. Cancer Inst. 2018 Dec;110:1418-1421; Powers J et al. Cancer Res. 2020 09;80:3732-3744). Wasserman et al. examined TP53 alterations in pediatric cases of ACC, and showed that patients with alterations that have near-WT transactivation capacity were less likely to have a strong family history of cancer. This alteration is absent from the non-cancer cohort of the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91), and has been observed primarily in individuals of Ashkenazi Jewish descent (Powers J et al. Cancer Res. 2020 09;80:3732-3744; Ambry internal data). This amino acid position is highly conserved in available vertebrate species and is predicted to be deleterious by in silico analysis. Based on current evidence, this alteration is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised. -

Jun 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 334 in the tetramerization domain of the TP53 protein and is located 7 nucleotides to the intron 9 splice acceptor site. This variant alters the conserved glycine residue that connects a short beta-strand (Glu326-Arg333) and an alpha-helix (Arg335-Gly356) of each subunit of the tetramer by facilitating a sharp turn (PMID: 20516128, 26572807). Computational prediction suggests that this variant may have deleterious impact on protein structure and function. One functional study has shown this variant to cause partial defects in transactivation of a subset of target genes and protein stability (PMID: 32675277). Other functional studies performed in yeast assays and ex vivo cultured cells have shown that this variant has neutral effect on the tetramer formation and transactivation function of the TP53 protein (PMID: 12826609, 25584008, 29955864). It has also been shown that the mutant protein does not exhibit dominant negative effect or loss of TP53 function in a human cell growth suppression assay (PMID: 30224644). This variant has been observed in eight individuals meeting Chompret criteria for Li-Fraumeni syndrome, including five individuals with childhood-onset adrenal cortical carcinoma (PMID: 23580068, 25503501, 25584008, 32675277). This variant has shown incomplete penetrance in a study of seven families (13 affected carriers and 9 unaffected carriers, PMID: 25584008, 32675277). This variant has also been observed in individuals affected with breast cancer, ovarian cancer, pancreatic cancer, pituitary cancer and skin cancer (PMID: 24448499, 25452441, 25503501, 32675277). Affected individuals were primarily of Ashkenazi Jewish ancestry. This variant has been identified in 1/250586 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. -

Li-Fraumeni syndrome 1 Pathogenic:1 Uncertain:1

Apr 11, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25584008, 32675277]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 25584008, 32675277]. -

Apr 25, 2018

Counsyl

Significance: Uncertain significance

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. -

not provided Uncertain:2

Jan 31, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000004 (1/250586 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with adrenocortical tumors (PMID: 32675277 (2020)), and individuals with breast and/or ovarian cancer, many of whom meet Chompret criteria (PMIDs: 23580068 (2013), 24448499 (2014), 25452441 (2015), 25503501 (2015), 25584008 (2015), and 27153395 (2016)). Functional studies in yeast and human cell lines showed this variant can form tetramers, and transactivation capacity and colony reduction activity performed similar to wild type (PMID: 12826609 (2003), 25584008 (2015), 29955864 (2018), 30224644 (2018), 32675277 (2020)). The variant has also been reported to segregate with disease in multiple affected members from several families (PMID: 32675277 (2020)), as well as reported as a low penetrance founder variant in the Ashkenazi Jewish population (PMID:32675277 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 21, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with adrenocortical tumors or breast cancer who meet Chompret criteria, but also in several others whose personal and family histories are not suspicious for Li-Fraumeni syndrome (Ribeiro 2012, Rath 2013, Kanchi 2014, Couch 2015, Maxwell 2016, Powers 2020); Published functional studies demonstrate no impact on tetramer formation, colony formation, or cellular localization, normal or mildly impaired growth suppression, no dominant negative effect, and primarily functional transactivation; one study reported decreased thermal stability, but lacked positive controls (Kato 2003, Kawaguchi 2005, Wasserman 2015, Giacomelli 2018, Fischer 2018, Pinto 2020, Powers 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25452441, 22040600, 24665023, 16007150, 23580068, 24448499, 25584008, 25503501, 27153395, 29955864, 32675277, 15510160, 30224644, 12826609, 32637605, 35043155, 32817165, 33300245, 34793697, 33449224) -

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 Uncertain:1

May 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;.;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;.;.;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.4	.;.;.;M;.;M;.;.
PhyloP100		6.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.0	.;.;.;D;.;D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;.;D;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;D;.;.
Vest4		0.89
MutPred		0.90		.;.;.;Gain of MoRF binding (P = 0.0278);.;Gain of MoRF binding (P = 0.0278);.;.;
MVP		1.0
MPC		0.41
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Varity_R		0.98
gMVP		0.81
Mutation Taster		=11/89	disease causing

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: rs730882028; hg19: chr17-7574027;