17-7676564-C-G

Variant names:

• chr17-7676564-C-G
• rs201382018
• NM_000546.6:c.31G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000546.6(TP53):​c.31G>C​(p.Glu11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,940 control chromosomes in the GnomAD database, including 1 homozygotes. 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. E11K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:10 O:1
• Conservation: PhyloP100: 2.06
• Publications: 87 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1873118).
• BP6: Variant 17-7676564-C-G is Benign according to our data. Variant chr17-7676564-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41723.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000592 (9/152106) while in subpopulation EAS AF = 0.00155 (8/5172). AF 95% confidence interval is 0.000769. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 9 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.31G>C	p.Glu11Gln	missense	Exon 2 of 11	NP_000537.3
	TP53	NM_001126112.3		c.31G>C	p.Glu11Gln	missense	Exon 2 of 11	NP_001119584.1	K7PPA8
	TP53	NM_001407262.1		c.31G>C	p.Glu11Gln	missense	Exon 3 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.31G>C	p.Glu11Gln	missense	Exon 2 of 11	ENSP00000269305.4	P04637-1
	TP53	ENST00000445888.6	TSL:1	c.31G>C	p.Glu11Gln	missense	Exon 2 of 11	ENSP00000391478.2	P04637-1
	TP53	ENST00000455263.6	TSL:1	c.31G>C	p.Glu11Gln	missense	Exon 2 of 12	ENSP00000398846.2	P04637-3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151988 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 250748 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1461834 Hom.: 1 Cov.: 35 AF XY: 0.000140 AC XY: 102 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00451 AC: 179 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41494

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	1	2	not provided (3)
-	1	2	not specified (3)
-	1	1	Li-Fraumeni syndrome (3)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Li-Fraumeni syndrome 1 (1)
-	-	1	TP53-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.19	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.1
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.45
Sift	Benign	0.038	D
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.90
MPC		1.6
ClinPred		0.22	T
GERP RS		5.4
PromoterAI		0.070	Neutral
Varity_R		0.12
gMVP		0.19
Mutation Taster		=2/98	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: rs201382018; hg19: chr17-7579882; COSMIC: COSV52746799; COSMIC: COSV52746799;