17-7676152-C-CG

Variant names:

• chr17-7676152-C-CG
• rs730882018
• NM_000546.6:c.216dupC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000546.6(TP53):​c.216dupC​(p.Val73ArgfsTer76) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -0.628

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7676152-C-CG is Pathogenic according to our data. Variant chr17-7676152-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 182957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.216dupC	p.Val73ArgfsTer76	frameshift_variant	Exon 4 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.216dupC	p.Val73ArgfsTer76	frameshift_variant	Exon 4 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461028 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726826

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:3

Jun 18, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TP53 c.216dup (p.Val73ArgfsTer76) change inserts one nucleotide to cause a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay and functional studies support a loss of p53 function (PMID: 28369373). That variant has been reported in individuals meeting clinical criteria for Li-Fraumeni syndrome (PMID: 1565143, internal data). It is absent in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). In summary, this variant meets criteria to be classified as pathogenic. -

Feb 12, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Jun 18, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication of one nucleotide in TP53 is denoted c.216_217insC (aka c.216dupC) at the cDNA level and p.Val73ArgfsX76 (V73RfsX76) at the protein level. The normal sequence, with the bases that are inserted in brackets, is TCCCCCC[C]GTGG. The duplication causes a frameshift, which changes a Valine to an Arginine at codon 73 in exon 4, and creates a premature stop codon at position 76 of the new reading frame. This mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. TP53 c.216_217insC has been observed in an individual with osteosarcoma with a family history of early-onset breast cancer (Toguchida 1992). We consider this mutation to be pathogenic. Mosaicism for TP53 mutations has been reported in at least three patients, all of whom had cancer themselves and none of whom had a family history significant for Li Fraumeni syndrome (Prochazkova 2009, Walsh 2011, Mitchell 2013). A pathogenic mutation in this gene is indicative of Li-Fraumeni syndrome (LFS), an autosomal dominant condition associated with a high-risk for a broad range of childhood- and adult-onset cancers. The following core cancer types account for 70-77% of LFS-associated tumors (in order of frequency): breast cancer, soft tissue sarcoma, brain tumors, osteosarcoma, and adrenocortical carcinoma (Gonzalez 2009, Olivier 2003, Ruijs 2010). Other types of cancer that have been reported to be associated with LFS include ovarian, gastrointestinal, pancreatic, genitourinary, skin, thyroid and lung cancers as well as leukemia, lymphoma, and neuroblastomas. Age-related and sex-specific cancer risks have been reported. According to one study, the overall risks for males with LFS to develop cancer by ages 16, 45, and 85 are estimated to be 19%, 41%, and 73%, respectively, whereas the risks for females are estimated to be 12%, 84%, and 100%, respectively (Chompret 2000). The higher penetrance in females is due to the high incidence of breast cancer, accounting for 80% of the cancers in the age group of 16 to 45 years (Chompret 2000). The majority of LFS-associated breast cancers are HER2/neu positive ductal carcinomas (Melhem-Bertrandt 2012). The most common types of sarcomas in LFS are rhabdomyosarcomas before age 5 and osteosarcomas at any age (Ognjanovic 2012). LFS is associated with many types of brain tumors including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas, and they can occur in childhood or adulthood (Olivier 2003). Individuals with LFS who have been diagnosed with cancer have up to a 57% risk of a second primary cancer within 30 years of the first diagnosis and up to a 38% risk of a third primary diagnosis (Hisada 1998). Several studies have demonstrated that subsequent tumors often develop in the radiation field of the previously treated cancer (Chompret 2000, Hisada 1998). Approximately 24% of LFS cases result from a de novo, rather than inherited, mutation in the TP53 gene (Chompret 2000). This variant has been seen apparently mosaic. The variant is found in HEREDICANCER panel(s). -

Oct 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.216dupC pathogenic mutation, located in coding exon 3 of the TP53 gene, results from a duplication of C at nucleotide position 216, causing a translational frameshift with a predicted alternate stop codon (p.V73Rfs*76). In one study, this mutation was reported in the germline of a patient with osteosarcoma at age 15y, whose mother had breast cancer at age 25y (Toguchida J et al. N Engl J Med. 1992;326(20):130-18). This mutation has also been detected in a breast cancer patient diagnosed at age 27y and an unaffected 28y/o male. Functional studies demonstrated an ~50% decrease in p53 functionality score of lymphocytes as compared to wildtype (Zerdoumi Y et al. Hum Mol Genet. 2017 Jul 15;26(14):2812). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Li-Fraumeni syndrome Pathogenic:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val73Argfs*76) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with osteosarcoma and breast cancer (PMID: 1565143, 28369373). This variant is also known as a 1-bp insertion at codons 71-72. ClinVar contains an entry for this variant (Variation ID: 182957). For these reasons, this variant has been classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

May 15, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple myeloma Pathogenic:1

Aug 31, 2019

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Li-fraumeni-like syndrome Pathogenic:1

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TP53: PVS1, PM2, PS4:Moderate -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882018; hg19: chr17-7579470;