17-7674277-C-T

Variant names:

• chr17-7674277-C-T
• rs1064793603
• NM_000546.6:c.686G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PM1 PM5 BP4_Moderate BS2

The NM_000546.6(TP53):​c.686G>A​(p.Cys229Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,459,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C229S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 0.0690
• Publications: 67 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 -2 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 34 uncertain in NM_000546.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7674278-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 420137.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17732441).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

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.686G>A	p.Cys229Tyr	missense	Exon 7 of 11	NP_000537.3
	TP53	NM_001126112.3		c.686G>A	p.Cys229Tyr	missense	Exon 7 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.686G>A	p.Cys229Tyr	missense	Exon 8 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.686G>A	p.Cys229Tyr	missense	Exon 7 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.686G>A	p.Cys229Tyr	missense	Exon 7 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000610292.4	TSL:1	c.569G>A	p.Cys190Tyr	missense	Exon 6 of 10	ENSP00000478219.1	P04637-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1459958 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726410

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

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

European-Non Finnish (NFE) AF: 0.00000991 AC: 11 AN: 1110338

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Hereditary cancer-predisposing syndrome (4)
-	2	-	Li-Fraumeni syndrome (2)
-	1	-	Adrenocortical carcinoma, hereditary (1)
-	1	-	Li-Fraumeni syndrome 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Benign	0.25
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	-0.13	N
PhyloP100		0.069
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.39
Sift	Benign	0.84	T
Sift4G	Benign	0.93	T
Polyphen		0.31	B
Vest4		0.24
MutPred		0.62		Gain of phosphorylation at C229 (P = 0.023)
MVP		0.79
MPC		1.2
ClinPred		0.17	T
GERP RS		0.097
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.55
Mutation Taster		=37/63	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: rs1064793603; hg19: chr17-7577595; COSMIC: COSV52670028;