chr17-7675143-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BS2_SupportingBP4BS3_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

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:5

Conservation

PhyloP100: 0.371

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.469G>A	p.Val157Ile	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.469G>A	p.Val157Ile	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251306

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135874

show subpopulations

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:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727244

show subpopulations

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.:

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

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. -

Dec 10, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 24, 2023

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 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:1Benign:2

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). -

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. -

not provided

Uncertain:1Benign:1

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. -

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. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

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

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

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

MutationAssessor

Benign

1.2

.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.;.;.

PrimateAI

Benign

0.39

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over