NM_000546.6:c.245C>T

Variant names:

• chr17-7676124-G-A
• rs534447939
• NM_000546.6:c.245C>T

Variant summary

Our verdict is Likely benign. The variant received -8 ACMG points: 1P and 9B. BP4 PM2_Supporting BS3 BS2

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.245C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 82 (p.Pro82Leu). This variant has been observed in 4-7 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_Moderate; Internal Lab Contributors: SCV000215716.6). This variant has an allele frequency of 0.00003335 (5/59976 alleles) in the Admixed American 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 = 0.0708; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predictor score of [0.01] predicts that the variant has no impact on splicing (score threshold <0.210) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_moderate, PM2_Supporting BS3, BP4, (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000080/MONDO:0018875/009

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:8
• Conservation: PhyloP100: 0.780
• Publications: 42 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 -8 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.245C>T	p.Pro82Leu	missense	Exon 4 of 11	NP_000537.3
	TP53	NM_001126112.3		c.245C>T	p.Pro82Leu	missense	Exon 4 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.245C>T	p.Pro82Leu	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.245C>T	p.Pro82Leu	missense	Exon 4 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.245C>T	p.Pro82Leu	missense	Exon 4 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.128C>T	p.Pro43Leu	missense	Exon 3 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 250446 AF XY: 0.0000295

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1460694 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726628

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5154

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111650

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74434

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000255 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	2	Li-Fraumeni syndrome (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	1	-	Li-Fraumeni syndrome 1 (1)
-	1	-	Malignant tumor of breast (1)
-	-	1	Squamous cell carcinoma of the head and neck (1)
-	-	1	TP53-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	13
DANN	Benign	0.34
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.34	N
PhyloP100		0.78
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.57
Sift	Benign	0.070	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.47
MVP		0.97
MPC		0.66
ClinPred		0.034	T
GERP RS		-0.43
PromoterAI		-0.015	Neutral
Varity_R		0.052
gMVP		0.29
Mutation Taster		=0/100	disease causing

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: rs534447939; hg19: chr17-7579442; COSMIC: COSV53209087; COSMIC: COSV53209087;