NM_000546.6:c.97-3C>T

Variant names:

• chr17-7676275-G-A
• rs786203749
• NM_000546.6:c.97-3C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BS2_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, the clinical significance of TP53 c.97-3C>T is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000514/MONDO:0007903/009

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TP53 NM_000546.6 splice_region, intron
• Scores: Splicing: ADA: 0.0004744
• Clinical Significance: Uncertain significance reviewed by expert panel U:6 B:2
• Conservation: PhyloP100: 3.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.97-3C>T		splice_region_variant, intron_variant	Intron 3 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.97-3C>T		splice_region_variant, intron_variant	Intron 3 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461888 Hom.: 0 Cov.: 57 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Dec 05, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 05, 2021

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. -

Oct 12, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a C>T nucleotide substitution at the -3 position of intron 3 of the TP53 gene. Splice site prediction tools do not indicate that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Li-Fraumeni syndrome Uncertain:1 Benign:1

Nov 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a C>T nucleotide substitution at the -3 position of intron 3 of the TP53 gene. Splice site prediction tools do not indicate that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jul 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Oct 07, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.97-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250846 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.97-3C>T in individuals affected with Li-Fraumeni Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 187457). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Li-Fraumeni syndrome 1 Uncertain:1

Apr 02, 2021

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, the clinical significance of TP53 c.97-3C>T is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BS2_Supporting. -

not provided Uncertain:1

Apr 09, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted TP53 c.97-3C>T or IVS3-3C>T and consists of a C>T nucleotide substitution at the -3 position of intron 3 of the TP53 gene. This variant is not predicted to affect gene splicing. TP53 c.97-3C>T has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The cytosine (C) nucleotide that is altered is not conserved. Based on currently available information, it is unclear whether TP53 c.97-3C>T is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	11
DANN	Benign	0.35
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203749; hg19: chr17-7579593;