17-7673788-G-C

Position:

chr17-7673788-G-C

Variant summary

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

The NM_000546.6(TP53):c.832C>G(p.Pro278Ala) variant causes a missense 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. 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. P278S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17U:1

Conservation

PhyloP100: 10.0

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a region_of_interest Interaction with DNA (size 7) in uniprot entity P53_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7673788-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 17-7673788-G-C is Pathogenic according to our data. Variant chr17-7673788-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376645.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.832C>G	p.Pro278Ala	missense_variant	8/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.832C>G	p.Pro278Ala	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Carcinoma of esophagus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 06, 2020

Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Kato 2003, Kotler 2018) and very weak transactivation in a system in which TP53 activity is increased (Jordan 2010); Observed in individuals with TP53-related cancers referred for genetic testing at GeneDx and in published literature (Melhem-Bertrandt 2012, Churpek 2015, and Mirabello 2015); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29979965, 30720243, 20407015, 25896519, 25428789, 21761402, 30840781) -

Ovarian serous cystadenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Li-Fraumeni syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 20, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24076587, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Multiple myeloma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pancreatic adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2019

The p.P278A variant (also known as c.832C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 832. The proline at codon 278 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in a patient meeting Chompret criteira (personal communication). This alteration has also been reported in a 1 of 109 women diagnosed with breast cancer who underwent genetic testing for suspected germline TP53 mutations (Melhem-Bertrandt A et al. Cancer. 2012 Feb;118:908-13). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in functional studies in yeast and human cell lines (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Jordan JJ et al. Mol. Cancer Res., 2010 May;8:701-16; Wang B et al. Cell Death Differ., 2014 Apr;21:521-32). Additional studies showed this variant to be deficient in DNA binding, apoptosis induction, and growth suppression (Wang B et al. Cell Death Differ. 2014 Apr;21:521-32; Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8). Other alterations at this same amino acid position (p.P278S, p.P278T) have previously been reported in the germline of individuals diagnosed with Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2001 Apr; 38(4):253-7; Güran S et al. Cancer Genet. Cytogenet. 2005 Jul; 160(2):164-8; Speiser P et al. Br. J. Cancer. 1996 Jul; 74(2):269-73). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in DNA binding (Petty TJ et al. EMBO J. 2011 Jun;30:2167-76; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Neoplasm of the large intestine

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2023

This variant disrupts the p.Pro278 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 8688334, 11370630), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20407015, 24076587, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 376645). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 21761402, 25428789, 25896519, 27328919, 32817165; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 278 of the TP53 protein (p.Pro278Ala). 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

0.99

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

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

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.0

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.4

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

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0060

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

Sift4G

Pathogenic

0.0

D;T;T;T;T;T;T;D;D;D;D;D;D;D;D;D;D;D;T

Polyphen

1.0, 1.0

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

Vest4

0.93

MutPred

0.96

Gain of MoRF binding (P = 0.054);.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.054);.;Gain of MoRF binding (P = 0.054);Gain of MoRF binding (P = 0.054);Gain of MoRF binding (P = 0.054);.;.;Gain of MoRF binding (P = 0.054);.;.;.;

MVP

0.98

MPC

0.38

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.75

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

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

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