17-7676583-C-G

Variant names:

• chr17-7676583-C-G
• rs876658274
• NM_000546.6:c.12G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000546.6(TP53):​c.12G>C​(p.Pro4Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.88
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-7676583-C-G is Benign according to our data. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-7676583-C-G is described in CliVar as Likely_benign. Clinvar id is 1144950.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.88 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.12G>C	p.Pro4Pro	synonymous_variant	Exon 2 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.12G>C	p.Pro4Pro	synonymous_variant	Exon 2 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Benign:1

Mar 17, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.040
DANN	Benign	0.57
PhyloP100		-2.9
PromoterAI		-0.015	Neutral

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: rs876658274; hg19: chr17-7579901;