17-7676152-C-T

Variant names:

• chr17-7676152-C-T
• rs587782423
• NM_000546.6:c.217G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BS3 BS2

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.217G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 73 (p.Val73Met). 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; ClinVar SCV: SCV000186461.7). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.001037 (11/10608 alleles) in European (Finnish) population (PM2, BS1, and BA1 are not met). 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 (PMIDs: 12826609, 29979965, 30224644) (BS3). Computational predictor scores (BayesDel = -0.1673; 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 Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS3, BS2_Moderate, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000075/MONDO:0018875/009

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: -2.31
• Publications: 38 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: Benign. The variant received -9 ACMG points.

• 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.217G>A	p.Val73Met	missense	Exon 4 of 11	NP_000537.3
	TP53	NM_001126112.3		c.217G>A	p.Val73Met	missense	Exon 4 of 11	NP_001119584.1
	TP53	NM_001407262.1		c.217G>A	p.Val73Met	missense	Exon 5 of 12	NP_001394191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000269305.9	TSL:1 MANE Select	c.217G>A	p.Val73Met	missense	Exon 4 of 11	ENSP00000269305.4
	TP53	ENST00000445888.6	TSL:1	c.217G>A	p.Val73Met	missense	Exon 4 of 11	ENSP00000391478.2
	TP53	ENST00000610292.4	TSL:1	c.100G>A	p.Val34Met	missense	Exon 3 of 10	ENSP00000478219.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000679 AC: 17 AN: 250502 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461028 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 726826

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86220

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5494

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111576

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000170 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Li-Fraumeni syndrome (3)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Li-Fraumeni syndrome;C0677776:Hereditary breast ovarian cancer syndrome;C2931038:Familial pancreatic carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	0.48
DANN	Benign	0.54
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.056	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	-0.76	N
PhyloP100		-2.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.37
Sift	Benign	0.24	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.24		Gain of glycosylation at P72 (P = 0.0625)
MVP		0.79
MPC		0.65
ClinPred		0.032	T
GERP RS		-4.1
PromoterAI		0.022	Neutral
Varity_R		0.074
gMVP		0.16
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587782423; hg19: chr17-7579470; COSMIC: COSV53023392;