rs121912664

chr17-7670699-C-Achr17-7670699-C-Gchr17-7670699-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000546.6(TP53):c.1010G>T(p.Arg337Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). 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: not found (cov: 32)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.244

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 14 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-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 17-7670699-C-A is Pathogenic according to our data. Variant chr17-7670699-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.1010G>T	p.Arg337Leu	missense_variant	10/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.1010G>T	p.Arg337Leu	missense_variant	10/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. Functional studies indicate this variant impacts protein function [PMID: 9766574, 16007150, 19454241, 9704930, 10653977, 9704931, 20978130]. This variant is expected to disrupt protein structure [Myriad internal data, PMID: 20978130]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2023	The p.R337L variant (also known as c.1010G>T), located in coding exon 9 of the TP53 gene, results from a G to T substitution at nucleotide position 1010. The arginine at codon 337 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). This variant is in the tetramerization domain of the TP53 protein and was not able to form tetramers and had impaired transactivation capacity in yeast-based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Kawaguchi T et al. Oncogene. 2005 Oct;24:6976-81). A thermal denaturation study predicted that several tetramerization domain mutants, including p.R337L, are thermally unstable at or near body temperature, and the authors note that earlier studies showed that p53 proteins with the p.R337L mutation exhibit an overall decrease in DNA-binding and transactivation activity (Kamada, R et al. J Biol Chem. 2011 Jan 7;286(1):252-8). In addition, there are several well-known mutations at the same codon that have been observed in LFS kindreds, including the Brazilian founder mutation, p.R337H (Ribeiro et al. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9330-5; Garritano et al. Hum Mutat. 2010 Feb;31(2):143-50). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural analysis, this alteration is structurally deleterious (Ambry internal data). Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Neoplasm of ovary Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.12
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.97	D;D;.;.;.;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.071	T;T;D;D;D;D;D;D
Polyphen		0.99	.;.;.;D;.;D;.;.
Vest4		0.62
MutPred		0.83		.;.;.;Loss of MoRF binding (P = 0.0544);.;Loss of MoRF binding (P = 0.0544);.;.;
MVP		0.92
MPC		0.38
ClinPred		0.99	D
GERP RS		3.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.97
gMVP		0.69

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: rs121912664; hg19: chr17-7574017; COSMIC: COSV52665150; COSMIC: COSV52665150;