17-7673700-C-T

Variant names:

• chr17-7673700-C-T
• rs1131691039
• NM_000546.6:c.919+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_Supporting PS4_Moderate PP4_Moderate PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.919+1G>A is a TP53 variant within the canonical donor site of exon 8. This change is observed to produce aberrant transcripts encoding premature truncations predicted to induce nonsense-mediated decay. (PVS1 (RNA); PMID:17066464, 31092812). This variant has been reported in 1 proband meeting Classic criteria and 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points (PS4_Moderate; PMIDs: 29324801, 31081129, 20805372, ClinVar SCV001382474). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, ClinVar SCV001382474). This variant is absent from gnomAD v3.1.2 (non-cancer) and gnomAD v2.1.1 (non-cancer) (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PP4_Moderate, PS4_Moderate, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA397836247/MONDO:0018875/009

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 2.46
• Publications: 7 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: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.919+1G>A		splice_donor_variant, intron_variant	Intron 8 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.919+1G>A		splice_donor_variant, intron_variant	Intron 8 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:3

Aug 05, 2024

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.919+1G>A is a TP53 variant within the canonical donor site of exon 8. This change is observed to produce aberrant transcripts encoding premature truncations predicted to induce nonsense-mediated decay. (PVS1 (RNA); PMID: 17066464, 31092812). This variant has been reported in 1 proband meeting Classic criteria and 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points (PS4_Moderate; PMIDs: 29324801, 31081129, 20805372, ClinVar SCV001382474). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, ClinVar SCV001382474). This variant is absent from gnomAD v3.1.2 (non-cancer) and gnomAD v2.1.1 (non-cancer) (PM2_Supporting). In summary, this variant meets the criteria to be classified as PATHOGENIC for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PP4_Moderate, PS4_Moderate, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024). -

Jan 10, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria was used: PVS1, PP4_MOD, PS4_MOD, PM2_SUP. -

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 8 of the TP53 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 20805372, 29070607, 29324801). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 633606). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:2

May 21, 2019

Academic Center for Education, Culture and Research, Motamed Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Adrenocortical carcinoma, hereditary Pathogenic:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Feb 05, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple individuals with Li-Fraumeni syndrome or early-onset breast cancer (PMID: 19542078, 20805372, 23259501, 25896519, 30796655, 31081129); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19542078, 25896519, 30703342, 30796655, 29263802, 25525159, 20805372, 28509937, 26681682, 23259501, 29324801, 17066464, 31081129, 30720243, 33300245, 33758026, 32191290, 31092812) -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 11, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.919+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the TP53 gene. This alteration has been reported in families meeting classic Li Fraumeni syndrome criteria and/or Chompret criteria for LFS (Marcel V et al. J Med Genet, 2009 Nov;46:766-72; Wilson JR et al. J Med Genet, 2010 Nov;47:771-4; Wong ESY et al. NPJ Genom Med, 2016 Jan;1:15003; Aceto GM et al. Breast Cancer Res Treat, 2019 Jun;175:479-485; Haque MM et al. Sci Rep, 2018 Aug;8:11705; Stoltze U et al. PLoS One, 2018 Jan;13:e0190050). This alteration has also been reported as a de novo observation with bilateral, metachronous breast cancer without mention of parental confirmation (O'Shea R et al. Fam Cancer, 2018 Jan;17:123-128). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

TP53-related disorder Pathogenic:1

Oct 01, 2024

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		2.5
GERP RS		3.8
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs1131691039; hg19: chr17-7577018; COSMIC: COSV52775982; COSMIC: COSV52775982;