17-7670709-C-G

Position:

• chr17-7670709-C-G

Variant summary

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

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:3 U:6
• Conservation: PhyloP100: 6.94

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got -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/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.1000G>C	p.Gly334Arg	missense_variant	10/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1000G>C	p.Gly334Arg	missense_variant	10/11	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

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250586 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135502

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2022	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2017	Variant summary: The TP53 c.1000G>C (p.Gly334Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/117018 control chromosomes at a frequency of 0.0000085, which does not exceed the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398). The variant has been reported in affected individuals in the literature with adrenocortical carcinoma, breast cancer and ovarian cancer, however strong evidence for causality was not included in these reports. Additionally, functional studies (transactivation induction and colony reduction studies) suggest the variant to have similar activity compared to WT (Wasserman_2015). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, until additional functional and clinical studies are available, this variant is classified as VUS. -

Li-Fraumeni syndrome 1 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 25, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 11, 2023	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]. -

Li-Fraumeni syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 182969). Advanced modeling performed at Invitae incorporating data from internal and/or published 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 05, 2024	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) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

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 α-helix and β-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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 30, 2022

- -

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;.;.
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882028; hg19: chr17-7574027;