17-7676047-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. BS3_SupportingBP4PM2_SupportingBS2

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.322G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 108 (p.Gly108Ser). This variant has been observed in 4-7 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_Moderate; internal lab contributors). This variant received a total of 0.5 points across 1 proband (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000005932 (7/1180002 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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 = 0.0347; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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). 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_Moderate, PM2_Supporting, BS3_Supporting, BP4. (Bayesian Points: -3; VCEP specifications version 2.1; 1/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000114/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:9B:1

Conservation

PhyloP100: 0.902

Publications

60 publications found

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 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

TP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

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.322G>A	p.Gly108Ser	missense_variant	Exon 4 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.322G>A	p.Gly108Ser	missense_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251326

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460148

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4354

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:9Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2Benign:1

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.322G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 108 (p.Gly108Ser). This variant has been observed in 4-7 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_Moderate; internal lab contributors). This variant received a total of 0.5 points across 1 proband (PS4 not met; Internal lab contributors). This variant has an allele frequency of 0.000005932 (7/1180002 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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 = 0.0347; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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). 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_Moderate, PM2_Supporting, BS3_Supporting, BP4. (Bayesian Points: -3; VCEP specifications version 2.1; 1/16/2025). -

Jul 29, 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 glycine with serine at codon 108 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be functional (PMID: 12826609 and IARC database, 29979965, 30224644). This variant has been observed in an individual affected with osteosarcoma (PMID: 25896519) an has not been reported in individuals affected with Li-Fraumeni syndrome in the literature. This variant has been identified in 3/251326 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 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 108 of the TP53 protein (p.Gly108Ser). This variant is present in population databases (rs587782461, gnomAD 0.007%). This missense change has been observed in individual(s) with osteosarcoma (PMID: 25896519). ClinVar contains an entry for this variant (Variation ID: 142431). Invitae Evidence Modeling incorporating data from in vitro 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Oct 09, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate partially functional transactivation, no dominant-negative effect, and no impact on growth suppression activity (PMID: 12826609, 15825182, 29979965, 30224644); Observed in an individual with osteosarcoma (PMID: 25896519); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27311873, 12826609, 27049831, 27566247, 14559903, 15825182, 11733960, 29979965, 28861920, 30840781, 15781620, 26875746, 30224644, 25896519, 15510160) -

Jan 05, 2018

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Mar 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G108S variant (also known as c.322G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 322. The glycine at codon 108 is replaced by serine, an amino acid with similar properties. The p.G108S alteration has been reported as a somatic alteration twice and has been reported once as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum. Mutat. 2007 Jun; 28(6):622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation capacity and no dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul; 100(14):8424-9; Sakuragi N et al. Int. J. Cancer. 2005 Sep; 116(4):514-9). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (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, with serine being the reference amino acid in lamprey. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.G108S remains unclear. -

Jul 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with serine at codon 108 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown the mutant protein to be partiailly functional in yeast transcriptional transactivation assays and functional in human cell growth suppression and proliferation studies (PMID: 12826609, 29979965, 30224644). This variant has been observed in an individual affected with osteosarcoma (PMID: 25896519). This variant has been identified in 3/251326 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 specified

Uncertain:1

Apr 01, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TP53 c.322G>A (p.Gly108Ser) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251326 control chromosomes. c.322G>A has been reported in the literature in at-least one individual with an osteosarcoma (example: Mirabello_2015). This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least four publications report experimental evidence evaluating an impact on protein function. In these studies the variant demonstrated partially functional transactivation activity across eight different promoters and was shown to have no dominant negative effect in yeast-based assays, and in human cells, the variant was shown to retain its capability for growth suppression (example: Kato_2003, Sakuragi_2005, Giacomelli_2018, Kotler_2018). The following publications have been ascertained in the context of this evaluation (PMID: 30224644, 12826609, 15825182, 25896519, 29979965). ClinVar contains an entry for this variant (Variation ID: 142431). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Adrenocortical carcinoma, hereditary

Uncertain:1

Aug 24, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;D;.;D;.;.;.;.;.;.;D;.;.;D;D;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.88

D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.

PhyloP100

0.90

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.1

N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;D

REVEL

Uncertain

0.61

Sift

Benign

0.17

T;T;.;T;.;.;T;T;.;.;T;.;.;D;.;D

Sift4G

Benign

0.14

T;T;T;T;T;T;T;T;T;T;T;T;T;.;D;.

Polyphen

0.81

P;.;.;P;.;P;P;P;.;.;P;.;.;D;.;.

Vest4

0.29

MutPred

0.70

Gain of disorder (P = 0.0574);Gain of disorder (P = 0.0574);.;Gain of disorder (P = 0.0574);.;Gain of disorder (P = 0.0574);Gain of disorder (P = 0.0574);Gain of disorder (P = 0.0574);.;.;Gain of disorder (P = 0.0574);.;Gain of disorder (P = 0.0574);Gain of disorder (P = 0.0574);Gain of disorder (P = 0.0574);Gain of disorder (P = 0.0574);

MVP

0.92

MPC

1.1

ClinPred

0.56

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.42

gMVP

0.48

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over