rs730882014

Variant names:

• chr17-7676154-GG-CA
• rs730882014
• NM_000546.6:c.214_215delCCinsTG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.214_215delinsTG variant in TP53 is a deletion/insertion variant predicted to cause substitution of proline by cysteine at amino acid 72 (p.Pro72Cys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as variant of uncertain clinical significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting. (Bayesian Points: -1; VCEP specifications version 2.2; 2/6/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000069/MONDO:0018875/009

• Frequency: GnomAD MNV: 𝑓 0.000012 Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:8 B:1
• Conservation: PhyloP100: 1.44
• Publications: 9 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: 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.214_215delCCinsTG	p.Pro72Cys	missense_variant		ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.214_215delCCinsTG	p.Pro72Cys	missense_variant		1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

GnomAD MNV AF: 0.0000120 AC: 3 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 72 of the TP53 protein (p.Pro72Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 182953). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 06, 2025

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6: c.214_215delinsTG variant in TP53 is a deletion/insertion variant predicted to cause substitution of proline by cysteine at amino acid 72 (p.Pro72Cys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as variant of uncertain clinical significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, PM2_Supporting. (Bayesian Points: -1; VCEP specifications version 2.2; 2/6/2025). -

Li-Fraumeni syndrome 1 Uncertain:2

Apr 20, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 11, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Aug 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with cysteine at codon 72 of the TP53 protein. Experimental functional studies have reported this variant did not affect function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with colorectal cancer (PMID: 37761360). 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. -

Dec 11, 2019

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. -

not specified Uncertain:1

Dec 21, 2023

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.214_215delinsTG (p.Pro72Cys) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250672 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. p.Pro72Cys has been reported in the literature in one individuals affected with Colorectal Cancer (Alsolme_2023). The report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. 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: 37761360). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=6) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Nov 06, 2022

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 that this missense variant does not alter protein structure/function; Published functional studies demonstrate retention of growth suppression activity and no dominant-negative effect (Giacomelli 2018); This variant is associated with the following publications: (PMID: 30886117, 26340530, 30224644, 15510160) -

TP53-related disorder Uncertain:1

May 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TP53 c.214_215delinsTG variant is predicted to result in an in-frame deletion and insertion. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182953/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

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

Other links and lift over

dbSNP: rs730882014; hg19: chr17-7579472; COSMIC: COSV105026609;