chr17-7675089-G-A

Variant names:

• chr17-7675089-G-A
• rs138729528
• NM_000546.6:c.523C>T
• TP53 p.Arg175Cys

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM5PP3_Moderate

The NM_000546.6(TP53):c.523C>T (p.Arg175Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000681 (AC=11) in the gnomAD database across 1,614,206 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000207. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★★). ClinVar reports functional evidence for this variant: "SCV000833097: Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID:12826609, 29979965, 30224644, 33245408).". A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R175H: Pathogenic (ClinVar VariationId 12374, 3 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R175?: Uncertain_significance (ClinVar VariationId 2687679, 0 stars); p.R175= (synonymous): Benign/Likely_benign (ClinVar VariationId 1527986, 2 stars) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 570 samples carry this exact amino acid change out of 2850 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:10
• Conservation: PhyloP100: 4.04
• Publications: 74 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for TP53 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000833097: Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644, 33245408).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 38 pathogenic, 5 benign (OR vs. background: 35.0).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R175H: Pathogenic (ClinVar VariationId 12374, 3 stars); Other variants at the same amino acid residue (not pathogenic): p.R175?: Uncertain_significance (ClinVar VariationId 2687679, 0 stars); p.R175= (synonymous): Benign/Likely_benign (ClinVar VariationId 1527986, 2 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TP53 NM_000546.6	MANE Select	c.523C>T p.Arg175Cys	missense	Exon 5 of 11	Prot: NP_000537.3
	TP53 NM_001126112.3		c.523C>T p.Arg175Cys	missense	Exon 5 of 11	Prot: NP_001119584.1 UniProt:
	TP53 NM_001407262.1		c.523C>T p.Arg175Cys	missense	Exon 6 of 12	Prot: NP_001394191.1 UniProt:

TP53 NM_000546.6

MANE Select

HGVSc / HGVSpc.523C>Tp.Arg175Cys

Exon rankExon 5 of 11

missense

Prot: NP_000537.3

TP53 NM_001126112.3

HGVSc / HGVSpc.523C>Tp.Arg175Cys

Exon rankExon 5 of 11

missense

Prot: NP_001119584.1UniProt: K7PPA8P04637-1

TP53 NM_001407262.1

HGVSc / HGVSpc.523C>Tp.Arg175Cys

Exon rankExon 6 of 12

missense

Prot: NP_001394191.1UniProt: K7PPA8P04637-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TP53 ENST00000269305.9	TSL:1MANE Select	c.523C>T p.Arg175Cys	missense	Exon 5 of 11	Prot: ENSP00000269305.4 UniProt:
	TP53 ENST00000445888.6	TSL:1	c.523C>T p.Arg175Cys	missense	Exon 5 of 11	Prot: ENSP00000391478.2 UniProt:
	TP53 ENST00000610292.4	TSL:1	c.406C>T p.Arg136Cys	missense	Exon 4 of 10	Prot: ENSP00000478219.1 UniProt:

TP53 ENST00000269305.9

TSL:1MANE Select

HGVSc / HGVSpc.523C>Tp.Arg175Cys

Exon rankExon 5 of 11

missense

Prot: ENSP00000269305.4UniProt: P04637-1

TP53 ENST00000445888.6

TSL:1

HGVSc / HGVSpc.523C>Tp.Arg175Cys

Exon rankExon 5 of 11

missense

Prot: ENSP00000391478.2UniProt: P04637-1

TP53 ENST00000610292.4

TSL:1

HGVSc / HGVSpc.406C>Tp.Arg136Cys

Exon rankExon 4 of 10

missense

Prot: ENSP00000478219.1UniProt: P04637-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152204	Cov:33
GnomAD2 exomes	AF: 0.0000159	AC:4	Hom:	AN:251284	Cov:
GnomAD4 exome	AF: 0.00000547	AC:8	Hom:0	AN:1461884	Cov:35
GnomAD4 genome	AF: 0.0000197	AC:3	Hom:0	AN:152322	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:51978	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122282	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000312 *	3	9622	0.00 *	0	10428
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000102	1	98004	0.00000620	1	161300

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	2	-	Li-Fraumeni syndrome (4)
-	2	-	Hereditary cancer-predisposing syndrome (2)
1	1	-	Li-Fraumeni syndrome 1 (2)
-	2	-	not provided (2)
-	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	not specified (1)
1	-	-	Ovarian neoplasm (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.97	D
FuncVEP CTI	Pathogenic	0.92
GPN-Star LLR	N/A	-8.3
GPN-Star score	N/A	8.3
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	0/100	disease causing
MutationAssessor	Pathogenic	2.9	M
PhyloP100	Uncertain	4.0
popEVE	Benign	-3.6
PrimateAI	Uncertain	0.71	T
PromoterAI	N/A	-0.022	Neutral
PROVEAN	Pathogenic	-7.7	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.95
VESM-3B	Benign	-11

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.11	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 no calibration

1 assay found for this variant.

No calibration: 1 assay (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Nucleotide level

Deep mutational scan of human TP53 in HCT116 colorectal cancer cells covering Exons 5, 6, 7 and 8

• Gene: TP53
• Score: -0.759

No calibration data

This score is at approximately the 22th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs138729528;

hg19: chr17-7578407;

COSMIC: COSV52688031;

COSMIC: COSV52688031;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar