17-7675200-C-G

Variant names:

• chr17-7675200-C-G
• rs28934875
• NM_000546.6:c.412G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PS4_Supporting PS3 PP3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.412G>C variant in TP53 is a missense variant predicted to cause substitution of alanine by proline at amino acid 138 (p.Ala138Pro). This variant has been reported in 1 proband/family meeting Classic LFS criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID:9569035). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID:34906512, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5846; Align GVGD = Class 25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3, PM2_supporting, PS4_supporting, PP4_moderate. (Bayesian Points: 9; VCEP specifications version 2.3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000166/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.90
• Publications: 85 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_pathogenic. The variant received 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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	c.412G>C	p.Ala138Pro	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.412G>C	p.Ala138Pro	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Jun 05, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.412G>C variant in TP53 is a missense variant predicted to cause substitution of alanine by proline at amino acid 138 (p.Ala138Pro). This variant has been reported in 1 proband/family meeting Classic LFS criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 9569035). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5846; Align GVGD = Class 25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3, PM2_supporting, PS4_supporting, PP4_moderate. (Bayesian Points: 9; VCEP specifications version 2.3). -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 138 of the TP53 protein (p.Ala138Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome-related cancers (adrenocortical carcinoma, rhabdomyosarcoma, chondrosarcoma, breast cancer) (PMID: 9569035, 17567834). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12376). 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%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 15548685, 17606709, 19958544, 21343334). This variant disrupts the p.Ala138 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 22507745, 32552660), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:1

Apr 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (PMID: 12826609, 21343334, 29979965, 30224644); 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: 17606709, 30840781, 15548685, 18765419, 20118236, 25847421, 30224644, 21343334, 19958544, 17567834, 25584008, 29753700, 29979965, 15510160, 9569035, 12826609) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 23, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A138P pathogenic mutation (also known as c.412G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 412. The alanine at codon 138 is replaced by proline, an amino acid with highly similar properties. This alteration has been identified in a family meeting Li-Fraumeni syndrome criteria (Sedlacek Z et al. Br J Cancer, 1998 Apr;77:1034-9) and also in two related individuals with medulloblastoma (Waszak SM et al. Lancet Oncol, 2018 06;19:785-798). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a 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 variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.1	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.7	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D
Polyphen		1.0	D;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.;.
Vest4		0.89
MutPred		0.95		Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;.;.;.;Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;.;Loss of helix (P = 0.079);.;.;.;.;Loss of helix (P = 0.079);.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.69
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28934875; hg19: chr17-7578518; COSMIC: COSV52661607; COSMIC: COSV52661607;