17-7676264-C-G

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:5 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	NM_000546.6	MANE Select	c.105G>C	p.Leu35Phe	missense	Exon 4 of 11	NP_000537.3
	TP53	NM_001126112.3		c.105G>C	p.Leu35Phe	missense	Exon 4 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.105G>C	p.Leu35Phe	missense	Exon 5 of 12	NP_001394191.1	K7PPA8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.105G>C	p.Leu35Phe	missense	Exon 4 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.105G>C	p.Leu35Phe	missense	Exon 4 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000455263.6	TSL:1	c.105G>C	p.Leu35Phe	missense	Exon 4 of 12	ENSP00000398846.2	P04637-3

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

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	1	Li-Fraumeni syndrome (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	1	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.094	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L
PhyloP100		-2.4
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.49
Sift	Benign	0.41	T
Sift4G	Benign	0.42	T
Polyphen		0.21	B
Vest4		0.047
MutPred		0.13		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;