rs121912661

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-7676264-C-A
• chr17-7676264-C-G
• chr17-7676264-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. BP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.105G>T variant in TP53 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 35 (p.Leu35Phe). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = -0.078; 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. Although SpliceAI predicts a weak potential splice effect, expert review suggests there is no impact on the native site, and following expert review the variant is considered to have no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BP4_Moderate. (Bayesian Points: -1; VCEP specifications version 2.0; date of approval) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000025/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• 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: Uncertain_significance. The variant received 0 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.105G>T	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>T	p.Leu35Phe	missense_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Carcinoma of pancreas Pathogenic:1

May 14, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Li-Fraumeni syndrome Uncertain:1

Sep 06, 2024

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.105G>T variant in TP53 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 35 (p.Leu35Phe). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = -0.078; 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. Although SpliceAI predicts a weak potential splice effect, expert review suggests there is no impact on the native site, and following expert review the variant is considered to have no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BP4_Moderate. (Bayesian Points: -1; VCEP specifications version 2.0; date of approval) -

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	3.3
DANN	Benign	0.81
DEOGEN2	Benign	0.018	T;T;D;.;.;.;D;.;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.84	T;T;.;T;T;.;T;T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.097	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		-0.00020	Neutral
Varity_R		0.32
gMVP		0.11
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -11

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: COSV53176324;