17-7676577-T-C

Variant names:

• chr17-7676577-T-C
• rs573130482
• NM_000546.6:c.18A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000546.6(TP53):​c.18A>G​(p.Ser6Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,816 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S6S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TP53 NM_000546.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.31
• Publications: 17 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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-7676577-T-C is Benign according to our data. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7676577-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 414037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.31 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.18A>G	p.Ser6Ser	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.18A>G	p.Ser6Ser	synonymous_variant	Exon 2 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250726 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461816 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727194

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Benign:3

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mar 31, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Hereditary cancer-predisposing syndrome Benign:3

Dec 08, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Benign:2

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 29, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TP53-related disorder Benign:1

Sep 13, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.88
DANN	Benign	0.54
PhyloP100		-2.3
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs573130482; hg19: chr17-7579895;