17-7675217-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):c.395A>G(p.Lys132Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,032 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K132N) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21
• 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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain 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 chr17-7675216-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376624.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.421
• PP5: Variant 17-7675217-T-C is Pathogenic according to our data. Variant chr17-7675217-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376625.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.395A>G	p.Lys132Arg	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.395A>G	p.Lys132Arg	missense_variant	5/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74250

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 28, 2023	The p.K132R variant (also known as c.395A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 395. The lysine at codon 132 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported as a somatic mutation 65 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This variant is in the critically functional DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and dominant negative effect in yeast based assays (Kato S et al., Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth L et al., Carcinogenesis 2007 Feb; 28(2):289-98). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 132 of the TP53 protein (p.Lys132Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni Syndrome (PMID: 29753700; Invitae). ClinVar contains an entry for this variant (Variation ID: 376625). 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, 29979965, 30224644). This variant disrupts the p.Lys132 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 18989156; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Glioblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Adrenal cortex carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Carcinoma of esophagus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma 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

- -

Ovarian serous cystadenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Uterine carcinosarcoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Li-Fraumeni syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 13, 2024

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 16861262, 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

- -

Neoplasm of ovary Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

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

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of uterine cervix Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.79	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
ClinPred		0.98	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		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: rs1057519996; hg19: chr17-7578535; COSMIC: COSV52666637; COSMIC: COSV52666637;