rs1555526470

chr17-7675992-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Strong PM2 PP3_Moderate PP5_Very_Strong

The NM_000546.6(TP53):c.375+1_375+2insG variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 splice_donor
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.36

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.23519458 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.6, offset of 1, new splice context is: cggGTcagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-7675992-A-AC is Pathogenic according to our data. Variant chr17-7675992-A-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 528263.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.375+1_375+2insG		splice_donor_variant		ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.375+1_375+2insG		splice_donor_variant		1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 13, 2024	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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 29, 2019	The c.375+1dupG intronic pathogenic mutation, results from the duplication of one nucleotide at nucleotide position 375 after intron 3 of the TP53 gene. This alteration was reported in an individual with breast cancer at 34 years of age who has a family member with sarcoma (Manoukian S et al. Eur. J. Cancer, 2007 Feb;43:601-6). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to shift the native donor site by one nucleotide leading to a frameshift. This prediction is supported by preliminary RNA evidence (Ambry internal data). Another alteration at this same splice donor site (c.375+1G>A) has been reported in a family with early-onset bilateral breast cancer, leukemia, and a CNS tumor as well as in a female patient diagnosed with adrenal cortical carcinoma at age 11 months (Frebourg T et al. Am J Hum Genet. 1995 Mar;56(3):608-15; Pinto EM et al. Nat Commun. 2015 Mar 6;6:6302). In addition to the data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. -

Li-Fraumeni syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 528263). Disruption of this splice site has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 17224268). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 4 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). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2019

Canonical splice site variant predicted to result in an in-frame deletion of a critical region including the transactivation domain, SH3 domain, and the DNA binding domain (Bode 2004, Pessoa 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17224268) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 1
DS_DL_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555526470; hg19: chr17-7579310;