17-7675143-C-T

Variant names:

• chr17-7675143-C-T
• rs121912654
• NM_000546.6:c.469G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BS3_Supporting BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000546.6:c.469G>A variant in TP53 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 157 (p.Val157Ile). This variant has been observed in at least 2 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_Supporting; Internal Contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.057; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, BS3_supporting, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.0, 1/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000220/MONDO:0018875/009

• 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:5 B:5
• Conservation: PhyloP100: 0.371
• Publications: 430 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: Likely_benign. The variant received -3 ACMG points.

• BP4: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.469G>A	p.Val157Ile	missense	Exon 5 of 11	NP_000537.3
	TP53	NM_001126112.3		c.469G>A	p.Val157Ile	missense	Exon 5 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.469G>A	p.Val157Ile	missense	Exon 6 of 12	NP_001394191.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.469G>A	p.Val157Ile	missense	Exon 5 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.469G>A	p.Val157Ile	missense	Exon 5 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.352G>A	p.Val118Ile	missense	Exon 4 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251306 AF XY: 0.0000368

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112012

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000272 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:5 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Aug 06, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 10, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Aug 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 27, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with isoleucine at codon 157 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Experimental studies have shown that this variant is functional in yeast transcriptional transactivation studies, and human cell growth suppression and proliferation assays (PMID: 12826609, 15781620, 29979965, 30224644). This variant has been reported in individuals affected with sarcoma in the literature (PMID: 23894400) and in individuals affected with breast and colorectal cancer (PMID: 28202063, 31748977, 32998877, 34198491). 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:2

Mar 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 16, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6:c.469G>A variant in TP53 is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 157 (p.Val157Ile). This variant has been observed in at least 2 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_Supporting; Internal Contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.057; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, BS3_supporting, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.0, 1/16/2025).

not provided Uncertain:1 Benign:1

Oct 21, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 18, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not specified Benign:1

Jan 17, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.37
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.33	N
REVEL	Uncertain	0.42
Sift	Benign	0.75	T
Sift4G	Benign	0.70	T
Polyphen		0.76	P
Vest4		0.34
MVP		0.83
MPC		0.84
ClinPred		0.11	T
GERP RS		2.4
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.11
Mutation Taster		=2/98	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: rs121912654; hg19: chr17-7578461; COSMIC: COSV52676009; COSMIC: COSV52676009;