rs1131691004

chr17-7676039-A-ACGGAAAC

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.329_330insGTTTCCG(p.Leu111PhefsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R110R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.604

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 17-7676039-A-ACGGAAAC is Pathogenic according to our data. Variant chr17-7676039-A-ACGGAAAC is described in ClinVar as [Pathogenic]. Clinvar id is 428860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.329_330insGTTTCCG	p.Leu111PhefsTer40	frameshift_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.329_330insGTTTCCG	p.Leu111PhefsTer40	frameshift_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 12, 2024	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2017	The c.323_329dupGTTTCCG pathogenic mutation, located in coding exon 3 of the TP53 gene, results from a duplication of GTTTCCG at nucleotide position 323, causing a translational frameshift with a predicted alternate stop codon (p.L111Ffs*40). This mutation was previously reported in a kindred of Mexican descent with Li Fraumeni syndrome. The index case was diagnosed with breast cancer at age 23, her father had a history of a leiomyosarcoma diagnosed at age 67, and a deceased paternal half-sister had bronchioalveolar carcinoma at age 25. The proband, her father, and an unaffected 42 year old sibling were found to carry this mutation (Taja-Chayeb et al. World J Sur Oncol. 2009 Dec 17;7:97). 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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2023

This variant is also known as c.329_330insGTTTCCG. This premature translational stop signal has been observed in individual(s) with breast cancer and Li-Fraumeni syndrome (PMID: 20017945, 28369373). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu111Phefs*40) 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). ClinVar contains an entry for this variant (Variation ID: 428860). For these reasons, this variant has been classified as Pathogenic. -

Acute myeloid leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

curation

Molecular Diagnostics Laboratory, University of Rochester Medical Center

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131691004; hg19: chr17-7579357;