17-7675218-T-G

Variant names:

• chr17-7675218-T-G
• rs747342068
• NM_000546.6:c.394A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000546.6(TP53):​c.394A>C​(p.Lys132Gln) 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). Synonymous variant affecting the same amino acid position (i.e. K132K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-7675218-T-G is Pathogenic according to our data. Variant chr17-7675218-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376628.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 rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.394A>C	p.Lys132Gln	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.394A>C	p.Lys132Gln	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:1

Feb 13, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 21188122, 25961455, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18989156]. -

Adrenocortical carcinoma, hereditary Pathogenic:1

May 30, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K132Q pathogenic mutation (also known as c.394A>C), located in coding exon 4 of the TP53 gene, results from an A to C substitution at nucleotide position 394. The lysine at codon 132 is replaced by glutamine, an amino acid with similar properties. This variant has been reported in a child with a personal history of adrenocortical carcinoma diagnosed at 18 months and osteosarcoma diagnosed at age 11 (Delaney HM et al. J Pediatr Hematol Oncol, 2008 Nov;30:803-6). 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). 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). Another variant at the same codon, p.K132R (c.395A>G), has been reported in medulloblastoma and breast cancer cohorts (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119; Waszak SM et al. Lancet Oncol., 2018 06;19:785-798; Yi D et al. Hum. Genomics, 2019 01;13:4). 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 has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Li-Fraumeni syndrome Uncertain:1

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 132 of the TP53 protein (p.Lys132Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TP53-related conditions (PMID: 18989156). ClinVar contains an entry for this variant (Variation ID: 376628). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). 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	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D;.;D;.;.;.;.;.;.;D;.;.;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D;D;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.94
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;.;.
Polyphen		1.0	D;.;.;D;.;D;P;D;.;.;D;.;.;D;.
Vest4		0.95
MutPred		0.97		Loss of methylation at K132 (P = 0.0292);Loss of methylation at K132 (P = 0.0292);.;Loss of methylation at K132 (P = 0.0292);.;Loss of methylation at K132 (P = 0.0292);Loss of methylation at K132 (P = 0.0292);Loss of methylation at K132 (P = 0.0292);.;.;Loss of methylation at K132 (P = 0.0292);.;.;.;Loss of methylation at K132 (P = 0.0292);
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.84

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

Other links and lift over

dbSNP: rs747342068; hg19: chr17-7578536; COSMIC: COSV52708494; COSMIC: COSV52708494;