17-7674254-T-C

Variant names:

• chr17-7674254-T-C
• rs730882004
• NM_000546.6:c.709A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000546.6(TP53):​c.709A>G​(p.Met237Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,670 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 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 P:1 U:5
• Conservation: PhyloP100: 7.94

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 8 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, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.709A>G	p.Met237Val	missense_variant	Exon 7 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.709A>G	p.Met237Val	missense_variant	Exon 7 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461670 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:2

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces methionine with valine at codon 237 in the DNA binding domain 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 the mutant protein to be partially functional in yeast transactivation assay (PMID: 12826609, DOI: 10.1182/blood-2019-124622), and non-functional in human cell growth assays and exhibit dominant negative effect (PMID: 29979965, 30224644). This variant and other missense variants occurring at the same codon, p.Met237Lys and p.Met237lIe, showed significantly reduced transcriptional activity in yeast assays (Fischer 2019, dissertation, University of Toronto). This variant has been reported in an individual affected with breast cancer and meeting clinical testing criteria for Li-Fraumeni syndrome (PMID: 26681312) and in an individual affected with early-onset bilateral breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 29875428). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in hereditary cancer conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Feb 28, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M237V variant (also known as c.709A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 709. The methionine at codon 237 is replaced by valine, an amino acid with highly similar properties. The p.M237V 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 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). TP53 p.M237V was reported in a woman with bilateral breast cancer at ages 22 and 41 (Turner SA et al. Genet Med, 2019 02;21:426-430). Based on internal structural analysis, p.M237V disrupts important hydrogen bonding interactions and the local structure of a functionally important loop near a zinc-binding motif within the DNA binding site of TP53 (Ambry internal data; Golovenko D et al. Structure. 2018 Sep 4;26(9):1237-1250; Lukman S et al. PLoS One. 2013 Nov 12;8(11); Butler JS and Loh SN. Biochemistry. 2003 Mar 4;42(8):2396-403; Bullock AN, Henckel J, Fersht AR. Oncogene. 2000 Mar 2;19(10):1245-56). This alteration was observed 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel in a patient who met LFS criteria, and has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Susswein LR et al. Genet Med, 2016 08;18:823-32; Ambry internal data). Another alteration at the same codon, p.M237I (c.711G>A), has been described in a classic Li Fraumeni syndrome (LFS) case (Fortes FP et al. Braz. J. Med. Biol. Res., 2015 Jul;48:610-5). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. -

not specified Uncertain:1

Mar 02, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted TP53 c.709A>G at the cDNA level, p.Met237Val (M237V) at the protein level,and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been reported as a somatic variantin multiple cancer types including breast, colon and lung (Vega 1997, Deissler 2004, Malhotra 2013). Although anothervariant at this residue, TP53 Met237Ile, has been shown to severely impact transactivation in yeast-based assays(Kato 2003, Dearth 2007, Monti 2011), TP53 Met237Val is reported as having partially functional transactivation in theInternational Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53Met237Val was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBIExome Sequencing Project). Since Methionine and Valine share similar properties, this is considered a conservativeamino acid substitution. TP53 Met237Val occurs at a position that is conserved across species and is located in theDNA-binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structureand function. Based on currently available evidence, it is unclear whether TP53 Met237Val is a pathogenic or benignvariant. We consider it to be a variant of uncertain significance. -

Li-Fraumeni syndrome 1 Uncertain:1

Jun 18, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Li-Fraumeni syndrome Uncertain:1

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 237 of the TP53 protein (p.Met237Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 26681312, 28973705). ClinVar contains an entry for this variant (Variation ID: 182934). Invitae Evidence Modeling incorporating data from in vitro 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	0.81
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	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	Uncertain	2.4	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;T;D;D;T;T;D;D;D;D;D;D;D;D;D;D;D;T;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D
Vest4		0.91
MutPred		0.89		Gain of catalytic residue at M237 (P = 0.0545);Gain of catalytic residue at M237 (P = 0.0545);.;.;.;.;.;.;.;Gain of catalytic residue at M237 (P = 0.0545);.;Gain of catalytic residue at M237 (P = 0.0545);Gain of catalytic residue at M237 (P = 0.0545);Gain of catalytic residue at M237 (P = 0.0545);.;.;Gain of catalytic residue at M237 (P = 0.0545);.;.;.;.;
MVP		0.97
MPC		0.39
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.67

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: rs730882004; hg19: chr17-7577572; COSMIC: COSV52701833; COSMIC: COSV52701833;