17-7674236-T-C

Position:

• chr17-7674236-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000546.6(TP53):​c.727A>G​(p.Met243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.672

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a turn (size 5) in uniprot entity P53_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.727A>G	p.Met243Val	missense_variant	7/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.727A>G	p.Met243Val	missense_variant	7/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 11, 2024	The p.M243V variant (also known as c.727A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 727. The methionine at codon 243 is replaced by valine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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 proficient at growth suppression and has no 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 amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	curation	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 12, 2024	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For TP53, we used the output of the Naïve Bayes classifier that synthesized data from four different TP53 MAVEs in Fayer et al. (2021) (PMID: 34793697). If the classifier predicted a variant to be "Functionally abnormal," the variant was assigned PS3 evidence and no BS3 evidence. If a variant was predicted to be "Functionally normal," BS3_moderate evidence was used with no PS3 evidence. This variant GRCh38:17:7674236:T>C was assigned evidence codes ['BS3_Moderate', 'BP4'] and an overall classification of Likely benign -

Li-Fraumeni syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2023	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 243 of the TP53 protein (p.Met243Val). 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: 406567). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 22, 2024	This missense variant replaces methionine with valine at codon 243 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 was neutral in yeast transcriptional transactivation studies and human cell growth and poliferation assays (PMID: 12826609, 29979965, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.48	T;T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Benign	0.047
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	.;.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.45	T;T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.99	D;.;.;.;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.;D
Vest4		0.28
MutPred		0.72		Gain of catalytic residue at M243 (P = 0.1247);Gain of catalytic residue at M243 (P = 0.1247);.;.;.;.;.;.;.;Gain of catalytic residue at M243 (P = 0.1247);.;Gain of catalytic residue at M243 (P = 0.1247);Gain of catalytic residue at M243 (P = 0.1247);Gain of catalytic residue at M243 (P = 0.1247);.;.;Gain of catalytic residue at M243 (P = 0.1247);.;.;.;.;
MVP		0.87
MPC		0.39
ClinPred		0.74	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.54

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: rs786203117; hg19: chr17-7577554; COSMIC: COSV52851538; COSMIC: COSV52851538;