rs863224683

chr17-7675224-G-Achr17-7675224-G-Cchr17-7675224-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000546.6(TP53):c.388C>T(p.Leu130Phe) variant causes a missense change. 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. L130D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 5.79

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 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 3 benign, 16 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 chr17-7675223-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 428873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-7675224-G-A is Pathogenic according to our data. Variant chr17-7675224-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216466.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.388C>T	p.Leu130Phe	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.388C>T	p.Leu130Phe	missense_variant	5/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2022	The p.L130F pathogenic mutation (also known as c.388C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 388. The leucine at codon 130 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in a patient diagnosed with breast cancer at age 31y who has no reported family history of cancer, in a female patient diagnosed with sarcoma and rectal cancer at age 39y who has a family history of pancreatic cancer, and in a patient diagnosed with colorectal cancer at age 17y who has a family history of three paternal aunts with early-onset breast cancer diagnosed at ages 23y, 37y, and 40y (Chompret A et al. J Med Genet. 2001 Jan;38(1):43-7; Pinto C et al. Fam Cancer. 2009;8(4):383-90; Pinto P et al. Breast Cancer Res Treat. 2016 Sep;159(2):245-56). 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; Chompret A et al. J Med Genet. 2001 Jan;38(1):43-7). 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 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 alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 30, 2022	This missense variant replaces leucine with phenylalanine at codon 130 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant is non-functional in yeast transactivation assays (IARC database; PMID: 12826609), non-functional in human cell proliferation assays (PMID: 29979965), and exhibits dominant-negative effect and loss of function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with breast cancer at the age of 31 (PMID: 11332399), an individual affected with sarcoma and rectal cancer at the age of 39 with a family history of pancreatic cancer (PMID: 19468865), and an individual affected with colorectal cancer at the age of 17 with a family history of early-onset breast cancer (PMID: 27553368). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Li-Fraumeni syndrome 1 Pathogenic:1 Uncertain: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: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 07, 2023

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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 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: 216466). This missense change has been observed in individual(s) with Li-Fraumeni syndrome and/or breast cancer (PMID: 11332399, 18511570, 19468865). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 130 of the TP53 protein (p.Leu130Phe). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 21, 2022

Variant summary: TP53 c.388C>T (p.Leu130Phe) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250352 control chromosomes. The variant was reported in the IARC databse with 16 somatic and 2 germline occurrences. c.388C>T has been reported in the literature in the germline setting in an patient with breast cancer with 5 unaffected sisters (Chomprehet_2001), a patient with suspected LFS (Pinto_2009), a patient with germline predisposition syndrome without other clinical details (Martin_2021), and in a patient with colorectal cancer with a family history of breast cancer (Pinto_2016). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The IARC database reports the variant as being non-functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays by Kato et al. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;.;D;.;.;.;.;.;.;D;.;.;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	D;D;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	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;D;D;.;.;D;.;.;D;.
Vest4		0.84
MutPred		0.98		Gain of methylation at K132 (P = 0.0835);Gain of methylation at K132 (P = 0.0835);.;Gain of methylation at K132 (P = 0.0835);.;Gain of methylation at K132 (P = 0.0835);Gain of methylation at K132 (P = 0.0835);Gain of methylation at K132 (P = 0.0835);.;.;Gain of methylation at K132 (P = 0.0835);.;.;.;Gain of methylation at K132 (P = 0.0835);
MVP		1.0
MPC		1.7
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.56

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

Other links and lift over

dbSNP: rs863224683; hg19: chr17-7578542; COSMIC: COSV52686543; COSMIC: COSV52686543;