rs121912665

Variant names:

• chr17-7674965-G-A
• rs121912665
• NM_000546.6:c.566C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7674965-G-A
• chr17-7674965-G-C
• chr17-7674965-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PM1 PP3_Moderate BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A189S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:6
• Conservation: PhyloP100: 8.06
• Publications: 81 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 -5 ACMG points.

• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 32 uncertain in NM_000546.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• BP6: Variant 17-7674965-G-A is Benign according to our data. Variant chr17-7674965-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12382.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 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 GnomAdExome4. There are 23 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 42 AD gene.

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.566C>T	p.Ala189Val	missense	Exon 6 of 11	NP_000537.3
	TP53	NM_001126112.3		c.566C>T	p.Ala189Val	missense	Exon 6 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.566C>T	p.Ala189Val	missense	Exon 7 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.566C>T	p.Ala189Val	missense	Exon 6 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.566C>T	p.Ala189Val	missense	Exon 6 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.449C>T	p.Ala150Val	missense	Exon 5 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251448 AF XY: 0.0000294

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00101 AC: 40 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000286 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome 1 Uncertain:3

Jul 24, 2014

Pathway Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Jul 20, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

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.

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.

not provided Uncertain:1 Benign: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 v4.9

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
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.79
Sift	Benign	0.046	D
Sift4G	Benign	0.065	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.86		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
Mutation Taster		=0/100	disease causing

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

Other links and lift over

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