17-7674291-C-T

Position:

• chr17-7674291-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.673-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 NM_000546.6 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.73

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 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.1, offset of 1, new splice context is: ggcctgtgttatctcctaAGttg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-7674291-C-T is Pathogenic according to our data. Variant chr17-7674291-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 379336.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.673-1G>A		splice_acceptor_variant		ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.673-1G>A		splice_acceptor_variant		1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change occurs 1 nucleotides before exon 7 of the TP53 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This variant is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Truncating variants in TP53 are known to be pathogenic. Also, donor and acceptor splice site variants as usual lead to a loss of protein function (PMID: 16199547). This variant has been described in the international literature in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID:379336). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 17, 2018	The c.673-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 6 of the TP53 gene. This mutation has been detected in two families meeting Chompret criteria: in one family, the proband was diagnosed with breast cancer at age 43y and her son was diagnosed with adrenocortical carcinoma at age 12y; in another family, the proband was diagnosed with bilateral breast cancer at ages 38y and 44y and endometrial cancer at age 43y and her son died of a brain tumor at age 17y (Bougeard G et al. J Med Genet. 2001 Apr;38(4):253-7; Heitzer E et al. BMC Med Genet. 2013 Dec 29;14:129; Zebisch A et al. Blood. 2016 Nov 3;128(18):2270-2272). cDNA analysis indicate that this alteration results in partial retention of intron 6 due to the activation of a cryptic site (Bougeard G et al. J Med Genet. 2001 Apr;38(4):253-7). In addition to the clinical 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. -

not provided Pathogenic:1 Other:1

not provided, no classification provided	in vitro	MutSpliceDB: a database of splice sites variants effects on splicing, NIH	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2023	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Identified in patients tested at GeneDx and in published literature with personal and/or family history of Li-Fraumeni syndrome-related tumors (Bougeard et al., 2001; Heizter et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11370630, 20075707, 25525159, 28706968, 31867841, 32910176, 20522432, 31275557, 31581548, 34257334, 30720243, 35709138, 27621308, 30546832, 32554069, 31159747, 32164171, 24373500) -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change affects an acceptor splice site in intron 6 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Li-Fraumeni syndrome (PMID: 11370630, 24373500, 27621308). ClinVar contains an entry for this variant (Variation ID: 379336). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Li-Fraumeni syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: -2
DS_AL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854073; hg19: chr17-7577609; COSMIC: COSV52662773; COSMIC: COSV52662773;