NM_000546.6:c.105G>C

Variant names:

• chr17-7676264-C-G
• rs121912661
• NM_000546.6:c.105G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. BP4 PM2_Supporting BS2_Supporting BS3

This summary comes from the ClinGen Evidence Repository: The NM_000546.6:c.105G>C variant in TP53 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 35 (p.Leu35Phe). This variant has been observed in 2-3 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_Supporting; Invitae). This variant has an allele frequency of 0.00001186 (14/1180022 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 functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0784742; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -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_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000024/MONDO:0007903/009

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:3
• Conservation: PhyloP100: -2.36
• Publications: 30 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.

• 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	c.105G>C	p.Leu35Phe	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	c.105G>C	p.Leu35Phe	missense_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461884 Hom.: 0 Cov.: 57 AF XY: 0.00000825 AC XY: 6 AN XY: 727242

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112008

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

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2 Benign:1

Sep 06, 2024

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6:c.105G>C variant in TP53 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 35 (p.Leu35Phe). This variant has been observed in 2-3 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_Supporting; Invitae). This variant has an allele frequency of 0.00001186 (14/1180022 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 functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0784742; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -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_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024). -

Mar 14, 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 leucine with phenylalanine at codon 35 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to exhibit normal function in transactivation assay in yeast (IARC database and PMID: 12826609) and in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with breast cancer (PMID: 27135926). This variant has been identified in 1/31370 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. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 35 of the TP53 protein (p.Leu35Phe). This variant is present in population databases (rs121912661, gnomAD 0.007%). This missense change has been observed in individual(s) with adenosarcoma and/or breast cancer (PMID: 28288110; internal data). ClinVar contains an entry for this variant (Variation ID: 142562). 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). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Dec 04, 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. -

Dec 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 leucine with phenylalanine at codon 35 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown the mutant protein to exhibit normal function in a yeast transcriptional transactivation assay (PMID: 12826609) and in a human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with breast cancer (PMID: 27135926). This variant has been identified in 1/31370 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

Sep 24, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TP53 c.105G>C; p.Leu35Phe variant (rs121912661) has been reported in the germline of an individual with breast cancer who had loss of the alternative allele in breast tumor and no concurrent mutations in BRCA1/BRCA2 (Davies 2017, Supplementary Table 4). It has also been reported in the tumor of a patient with hepatocellular carcinoma (Nishida 1993). This variant is reported in the IARC TP53 database as having functional transactivation activity (see link). It is classified as uncertain by multiple laboratories in ClinVar (Variation ID: 142562), and found in the general population with a low overall allele frequency of 0.003% (1/30928 alleles) in the Genome Aggregation Database. The leucine at codon 35 is weakly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Leu35Phe variant is uncertain at this time. REFERENCES Link to IARC database: http://p53.iarc.fr/TP53GeneVariations.aspx Davies H et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017 Apr;23(4):517-525. Nishida N et al. Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res. 1993 Jan 15;53(2):368-72. -

not provided Benign:1

Jun 11, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18199664, 16546179, 8093350, 26617922, 30840781, 14559903, 12826609, 28288110, 30224644) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	0.43
DANN	Benign	0.72
DEOGEN2	Benign	0.018	T;T;D;.;.;.;D;.;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.84	T;T;.;T;T;.;T;T;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.094	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	.;.;L;L;L;L;L;.;.;.;.
PhyloP100		-2.4
PROVEAN	Benign	-0.56	N;N;N;.;N;N;N;.;N;.;N
REVEL	Uncertain	0.49
Sift	Benign	0.41	T;T;T;.;T;T;T;.;T;.;D
Sift4G	Benign	0.42	T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.21	B;.;B;B;B;B;B;.;P;.;.
Vest4		0.047
MutPred		0.13		Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);
MVP		0.86
MPC		0.77
ClinPred		0.15	T
GERP RS		-1.4
PromoterAI		0.00060	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.32
gMVP		0.11
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs121912661; hg19: chr17-7579582; COSMIC: COSV53067699;