rs121912665

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PP3_ModerateBS1BS2

The NM_000546.6(TP53):​c.566C>T​(p.Ala189Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

8
8
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:6

Conservation

PhyloP100: 8.06
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1
In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000287 (42/1461864) while in subpopulation EAS AF= 0.00101 (40/39700). AF 95% confidence interval is 0.00076. There are 0 homozygotes in gnomad4_exome. There are 23 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
BS2
High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.566C>T p.Ala189Val missense_variant Exon 6 of 11 ENST00000269305.9 NP_000537.3 P04637-1K7PPA8Q53GA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkc.566C>T p.Ala189Val missense_variant Exon 6 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
33
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:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251448
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000287
AC:
42
AN:
1461864
Hom.:
0
Cov.:
35
AF XY:
0.0000316
AC XY:
23
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152180
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000290
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6Benign:6
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1 Uncertain:3
Apr 12, 2023
Myriad Genetics, Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Feb 25, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 24, 2014
Pathway Genomics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Jul 20, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Aug 30, 2019
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jul 31, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces alanine with valine at codon 189 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant to be functional in yeast transcriptional transactivation assays and human cell growth suppression and proliferation assays (PMID: 12826609, 17606709, 21343334, 29979965, 30224644). To our knowledge, this variant has not been reported in individuals affected with Li-Fraumeni syndrome in the literature. The variant has been observed in individuals affected with breast, colon, pancreatic, and fallopian tube cancers (PMID: 33309985, 33397043, 33471991, 33818021) but also in unaffected individuals (PMID: 30287823, 32980694, 33309985, 33471991). This variant has been identified in 6/251448 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 12, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 12, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 15644779, 21343334, 12524418, 29700339, 14559903, 27889902, 17417775, 23667851, 27374712, 23973262, 18363031, 25348012, 28861920, 24101221, 17727479, 27311873, 17606709, 28154273, 30840781, 12826609, 33257846, 30224644, 29979965, 15510160, 35218119, 32322110, 37352403, 29770616, 30287823, 31016814, 33818021, 33309985, 33397043, 34963807, 34273903, 36243179, 32019277, 30352134, 33932062, 35764097, 38368425, 32998877, Soussi2023[article], 35043155) -

Familial colorectal cancer Pathogenic:1
Feb 01, 2003
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Li-Fraumeni syndrome Uncertain:1
Jan 12, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 189 of the TP53 protein (p.Ala189Val). This variant is present in population databases (rs121912665, gnomAD 0.03%). This missense change has been observed in individual(s) with colon cancer, stomach cancer, lung cancer, breast cancer, and fallopian tube carcinoma (PMID: 12524418, 23667851, 27374712, 29770616, 30287823, 33309985). ClinVar contains an entry for this variant (Variation ID: 12382). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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 specified Benign:1
Dec 08, 2021
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.566C>T (p.Ala189Val) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 316270 control chromosomes. The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. c.566C>T has been reported in the literature in individuals affected with different type of cancer (examples: Miyaki_2003, Cho_2013, Park_2016, Momozawa_2018, Shin_2020, Seo_2020, Fujita_2021, Alyami_2021 and Dorling _2021). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Functional studies report this variant showed no damaging effect of this variant (Monti_2011, Kato_2003). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign/benign (n=2) and as variant of uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1
Mar 30, 2022
Cancer Genomics Group, Japanese Foundation For Cancer Research
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Familial cancer of breast;C1835398:Li-Fraumeni syndrome 1 Benign:1
Jun 14, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.63
D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.1
.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.5
D;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;D
REVEL
Pathogenic
0.79
Sift
Benign
0.046
D;D;.;.;.;.;.;.;.;T;.;.;D;T;.;.;T;.;.;D;D
Sift4G
Benign
0.065
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen
1.0
D;.;.;.;.;.;.;.;.;P;.;P;D;P;.;.;P;.;.;.;D
Vest4
0.88
MutPred
0.86
Loss of disorder (P = 0.1065);Loss of disorder (P = 0.1065);.;.;.;.;.;.;.;Loss of disorder (P = 0.1065);.;Loss of disorder (P = 0.1065);Loss of disorder (P = 0.1065);Loss of disorder (P = 0.1065);.;.;Loss of disorder (P = 0.1065);.;.;.;.;
MVP
0.96
MPC
1.7
ClinPred
0.55
D
GERP RS
5.4
Varity_R
0.65
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.30
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.30
Position offset: -11

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.

Other links and lift over

dbSNP: rs121912665; hg19: chr17-7578283; COSMIC: COSV53050047; COSMIC: COSV53050047; API