17-7673312-A-G

Variant names:

• chr17-7673312-A-G
• rs3021068
• ENST00000420246.6:c.1021T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The ENST00000420246.6(TP53):​c.1021T>C​(p.Cys341Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,514 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C341G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TP53 ENST00000420246.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.611
• Publications: 58 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: Very rare variant in population databases, with high coverage
• BP6: Variant 17-7673312-A-G is Benign according to our data. Variant chr17-7673312-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 492638.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.993+223T>C		intron_variant	Intron 9 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.993+223T>C		intron_variant	Intron 9 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442514 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 716130

African (AFR) AF: 0.00 AC: 0 AN: 33176

American (AMR) AF: 0.00 AC: 0 AN: 41546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 39278

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101060

Other (OTH) AF: 0.00 AC: 0 AN: 59670

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Aug 17, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0067	.;T;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.31	T;T;T;.;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Uncertain	0.75	D
PhyloP100		0.61
PROVEAN	Benign	1.1	.;.;.;N;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	.;.;.;D;.
Polyphen		0.60	.;.;P;P;.
Vest4		0.36
MutPred		0.28		.;.;Gain of solvent accessibility (P = 0.0202);Gain of solvent accessibility (P = 0.0202);.;
MVP		0.84
ClinPred		0.12	T
GERP RS		1.3
PromoterAI		0.015	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3021068; hg19: chr17-7576630;