17-7670684-C-G

Position:

• chr17-7670684-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PP3 PM1_Supporting PS4_Moderate PS3 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.1025G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 342 (p.Arg342Pro). This variant has been reported in 3 unrelated families meeting Classic criteria. Based on this evidence, this variant scores 3 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs 25981898, 25226867, 19714490). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 3 families (PP1_Strong; PMIDs 25981898, 25226867, 19714490). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation, loss of growth suppression activity, and impaired tetramer formation indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 16007150). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = 0.24; Align GVGD = Class C35) 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). This variant has 8 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). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1_Strong, PS3, PM2_Supporting, PP3, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 9/6/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA337802/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: -0.406

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 Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1025G>C	p.Arg342Pro	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.1025G>C	p.Arg342Pro	missense_variant	10/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This missense variant is a single nucleotide substitution resulting in the replacement of amino acid arginine with proline at codon 342 of the TP53 protein. This variant is not present in population databases (ExAC no frequency). It has been reported in literature in Li-Fraumeni syndrome families (PMID: 25981898) and experimental studies have shown is pathogenic effect through inactivation of the TP53 protein (PMID: 20978130, PMID: 9766574, PMID: 19806023, PMID: 10064694). The mutation database ClinVar contains entries for this variant (Variation ID: 215996). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 12, 2023	The p.R342P pathogenic mutation (also known as c.1025G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1025. The arginine at codon 342 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in multiple families meeting classic LFS criteria (Fiszer-Maliszewska L, Fam. Cancer 2009 ; 8(4):541-6; Etzold A et al., Fam. Cancer 2015 Mar; 14(1):161-5; Kappel S et al. Breast Cancer Res Treat, 2015 Jun;151:671-8). This alteration has also been reported as a de novo finding in a patient with a personal history of rectal cancer diagnosed at age 25 and ovarian angiosarcoma diagnosed at age 35 (Crafton SM et al. Int J Gynecol Pathol, 2019 May;38:258-262). This alteration is located in the tetramerization domain, and renders the protein unable to form tetramers (Kawaguchi T, Oncogene 2005 Oct; 24(46):6976-81). Functional studies have indicated that this variant is deficient in transactivation activity in assays performed in both yeast and mammalian cells (Rollenhagen C, Int. J. Cancer 1998 Oct; 78(3):372-6; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Li-Fraumeni syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 21, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19714490, 25226867, 25981898]. This variant is expected to disrupt protein structure [PMID: 20978130]. Functional studies indicate this variant impacts protein function [PMID: 9766574, 19454241, 20978130]. -

Li-Fraumeni syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Sep 06, 2024	The NM_000546.6: c.1025G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 342 (p.Arg342Pro). This variant has been reported in 3 unrelated families meeting Classic criteria. Based on this evidence, this variant scores 3 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs 25981898, 25226867, 19714490). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 3 families (PP1_Strong; PMIDs 25981898, 25226867, 19714490). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation, loss of growth suppression activity, and impaired tetramer formation indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 16007150). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = 0.24; Align GVGD = Class C35) 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). This variant has 8 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). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1_Strong, PS3, PM2_Supporting, PP3, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 9/6/2024) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 342 of the TP53 protein (p.Arg342Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome cancers (PMID: 19714490, 25226867, 25981898). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215996). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 9766574, 10064694, 16007150, 19454241, 19806023, 20978130). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 24, 2024

Published functional studies demonstrate a damaging effect: non-functional transactivation and inability to form tetramers (PMID: 12826609, 20978130, 19806023, 19454241); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29620582, 23973262, 29085664, 10064694, 20978130, 19806023, 19454241, 9766574, 30720243, 25981898, 25226867, 33138793, 32817165, 12826609, 34654685, 31159747, 30840781, 33257846, 31105275, 30224644, 37864521, 19714490, 16007150, 15510160, Pessoa2014[Chapter], 11397945) -

Ovarian neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;.;.;D;.;D;.;.
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.93	D;D;.;.;.;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.4	.;.;.;M;.;M;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	.;.;.;N;.;N;.;.
REVEL	Pathogenic	0.65
Sift	Benign	0.066	.;.;.;T;.;T;.;.
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T
Polyphen		0.94	.;.;.;P;.;P;.;.
Vest4		0.58
MutPred		0.82		.;.;.;Loss of methylation at R342 (P = 0.0497);.;Loss of methylation at R342 (P = 0.0497);.;.;
MVP		0.98
MPC		0.40
ClinPred		0.86	D
GERP RS		2.4
Varity_R		0.97
gMVP		0.86

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: rs375338359; hg19: chr17-7574002; COSMIC: COSV52690857; COSMIC: COSV52690857;