chr17-7674887-C-T

Position:

chr17-7674887-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The ENST00000269305.9(TP53):c.644G>A(p.Ser215Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S215C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 6.16

Variant links:

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 links:

TP53 (HGNC:):

TP53 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 13 uncertain in ENST00000269305.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7674888-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1753522.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 17-7674887-C-T is Pathogenic according to our data. Variant chr17-7674887-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376662.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.644G>A	p.Ser215Asn	missense_variant	6/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.644G>A	p.Ser215Asn	missense_variant	6/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 15, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 14, 2023

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2024

The p.S215N variant (also known as c.644G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 644. The serine at codon 215 is replaced by asparagine, an amino acid with highly similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Li-Fraumeni syndrome (Ambry internal data). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 26, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 215 of the TP53 protein (p.Ser215Asn). This variant is not present in population databases (gnomAD no frequency). 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: 376662). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.5

.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.8

D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

Polyphen

1.0

D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D

Vest4

0.95

MutPred

0.93

Gain of catalytic residue at S215 (P = 0.1165);Gain of catalytic residue at S215 (P = 0.1165);.;.;.;.;.;.;.;Gain of catalytic residue at S215 (P = 0.1165);.;Gain of catalytic residue at S215 (P = 0.1165);Gain of catalytic residue at S215 (P = 0.1165);Gain of catalytic residue at S215 (P = 0.1165);.;.;Gain of catalytic residue at S215 (P = 0.1165);.;.;.;.;

MVP

0.94

MPC

1.6

ClinPred

0.99

GERP RS

5.3

Varity_R

0.96

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over