17-7675143-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1 PM5 BP6_Very_Strong BS2

The NM_000546.6(TP53):c.469G>A(p.Val157Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V157A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:5
• Conservation: PhyloP100: 0.371

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 Benign. Variant got -8 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000546.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7675141-GA-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3148383.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP6: Variant 17-7675143-C-T is Benign according to our data. Variant chr17-7675143-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 185404.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAdExome at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.469G>A	p.Val157Ile	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.469G>A	p.Val157Ile	missense_variant	5/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251306 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135874

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461884 Hom.: 0 Cov.: 35 AF XY: 0.0000151 AC XY: 11 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 29, 2023	The p.V157I variant (also known as c.469G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 469. The valine at codon 157 is replaced by isoleucine, an amino acid with highly similar properties. This variant was observed in an adult-onset sarcoma patient; however, no loss of heterozygosity was detected in this individual's tumor (Mitchell G et al. PLoS ONE 2013 Jul;8(7):e69026). This variant has also been reported in breast cancer patients (Jalkh N et al. BMC Med. Genomics. 2017 Feb 15;10(1):8; Petry V et al. Fam Cancer, 2020 01;19:47-53). This alteration is located in the DNA binding domain. Alterations at the same codon (p.V157D, p.V157A, p.V157F) have been reported in families meeting Li-Fraumeni and/or Li-Fraumeni-like syndrome criteria and are anticipated to result in a significant decrease in structural stability of the DNA-binding domain (Calhoun S et al. Biochemistry 2011 Jun;50:5345-53; Cho Y et al. Science 1994 Jul; 265(5170):346-55; Kitayner et al. Nat. Struct. Mol. Biol. 2010 Apr;17(4):423-9; Wang Z et al. Cancer Lett. 2014 Jan;342:36-42). However, the p.V157I variant showed only partially reduced transactivation capacity in comparison to wild type in a yeast-based functional assay (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Further, studies conducted in human cell lines indicate this alteration remains proficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species, and isoleucine is the reference amino acid in multiple species. In addition, this alteration is predicted to be tolerated by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 24, 2023	This missense variant replaces valine with isoleucine at codon 157 of the TP53 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Experimental studies have shown that this variant does not impact function in yeast transactivation assays (PMID: 12826609) or human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with sarcoma in the literature (PMID: 23894400, 28202063). This variant has been identified in 10/251306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Li-Fraumeni syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces valine with isoleucine at codon 157 of the TP53 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies are inconclusive regarding the effect of this change on protein function (PMID 12826609, 15781620, 30224644). This variant has been reported in individuals affected with cancer in the literature (sarcoma, PMID 23894400, 28202063). This variant has been identified in 10/251306 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2018	This variant is denoted TP53 c.469G>A at the cDNA level, p.Val157Ile (V157I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has been identified in individuals with sarcoma, early-onset breast cancer, and in a bone marrow sample from an individual with acute myeloid leukemia, as well as having been observed as a somatic variant in several different tumor types (Mitchell 2013, Forbes 2014, Hou 2015, Jalkh 2017). This variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Val157Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Val157Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2022	The frequency of this variant in the general population, 0.000087 (3/34588 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with leiomyosarcoma, breast cancer, and colorectal cancer (PMIDs: 12826609 (2003), 23894400 (2013), 28202063 (2017), 31748977 (2020), and 32998877 (2021)). In addition, an experimental study in yeast determined this variant partially impairs TP53 transactivation activity (PMID: PMID: 12826609 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is disease causing or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 17, 2022

Variant summary: TP53 c.469G>A (p.Val157Ile) results in a conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome (4e-05 vs 4e-05), allowing no conclusion about variant significance. c.469G>A has been reported in the literature in individuals affected with sarcoma or breast cancer (e.g. Mitchell_2013, Liu_2021). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Fortuno_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS. However, an expert panel classified as this variant as likely benign (ClinVar database). Based on the evidence outlined above, the variant was classified as likely benign. -

Li-Fraumeni syndrome 1 Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Aug 26, 2020

This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained partial function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). Finally, this variant has been observed in at least 2 60+ year old females without a cancer diagnosis (BS2_Supporting; Ambry internal lab data; Invitae internal lab data). In summary, TP53 c.469G>A; p.Val157Ile meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4, BS3_supporting and BS2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.74	T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.96	N;N;N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.33	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.75	T;T;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.76	P;.;.;.;.;.;P;.;P;B;P;.;.;P;.;.;.;B;.
Vest4		0.34
MVP		0.83
MPC		0.84
ClinPred		0.11	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.11

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: rs121912654; hg19: chr17-7578461; COSMIC: COSV52676009; COSMIC: COSV52676009;