rs751253294

Variant names:

• chr17-7675237-C-CT
• rs751253294
• ENST00000504937.5:c.-23dupA

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS2

The NM_000546.6(TP53):​c.376-2dupA variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000198 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TP53 NM_000546.6 splice_acceptor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 6.01

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 Likely_benign. Variant got -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15566836 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of 0 (no position change), new splice context is: ctccttcctcttcctacaAGtac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 17-7675237-C-CT is Benign according to our data. Variant chr17-7675237-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185593.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2}.
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.376-2dupA		splice_acceptor_variant, intron_variant	Intron 4 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.376-2dupA		splice_acceptor_variant, intron_variant	Intron 4 of 10	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249574 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461638 Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18 AN XY: 727092

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: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74296

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000116 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Feb 05, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Feb 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376-2dupA variant in TP53 has not been previously reported in individuals with disease. It has been reported in ClinVar (Variation ID185593). This variant has been identified in 2/110468 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs751253294). This variant is located in the 3' splice region. Computational tools suggest an impact to splicing; however, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.376-2dupA variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3. -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31159747, 30352134, 33084842, 28452373, 29247016, 29522266, 29625052, 36451132, 33990091) -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2020

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 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a 1 nucleotide duplication at the -2 position in intron 4 of the TP53 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing, although this prediction has not been confirmed in published RNA studies. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in individuals affected with breast and endometrial cancer (PMID: 28452373, 29522266). This variant has been identified in 2/249574 chromosomes 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. -

not specified Uncertain:1

Aug 19, 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.376-2dupA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of TP53 function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site. One predict the variant abolishes a canonical 3' acceptor site. However, one study has shown this variant does not cause a functional defect in vitro (Butz_2023). The variant allele was found at a frequency of 2e-05 in 1613758 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome (2e-05 vs 4e-05), allowing no conclusion about variant significance. c.376-2dupA has been reported in the literature in one individual affected with endometrial cancer as well as individuals who were referred for testing with a hereditary cancer panel (examples: Spurdle_2017, Tsaousis_2019, Bilyalov_2022, Butz_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28452373, 31159747, 36290365, 37653074). ClinVar contains an entry for this variant (Variation ID: 185593). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

TP53-related disorder Uncertain:1

Jun 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TP53 c.376-2dupA variant is predicted to result in an intronic duplication. This variant was reported in two individuals in two cohort of studies for cancer predisposition syndrome (reported as likely pathogenic in Table S3, Bilyalov et al. 2022. PubMed ID: 36290365; reported as uncertain in Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant was reported in a patient with breast cancer (reported as uncertain in Table S2, Hauke et al. 2018. PubMed ID: 29522266) and in another patient with endometrial carcinoma (Table S2A, Huang et al. 2018. PubMed ID: 29625052; reported as uncertain in Table 1, Spurdle et al. 2017. PubMed ID: 28452373). This variant was detected in at least one patient in a large cohort study of analyzing cancer risk variants in patients with congenital heart disease (eTable 4, Morton et al. 2021. PubMed ID: 33084842) and was interpreted as uncertain in a gnomAD-based analysis (Table 2, de Andrade et al. 2019. PubMed ID: 30352134). In ClinVar, this variant is interpreted as likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/185593/). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7578555-C-CT). In summary, this variant is interpreted as variant of uncertain significance. -

Li-Fraumeni syndrome Benign:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -22

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

Publications

LitVar

Other links and lift over

dbSNP: rs751253294; hg19: chr17-7578555;