rs1287887419

Positions:

• chr17-7670625-T-A
• chr17-7670625-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP6

The NM_000546.6(TP53):​c.1084A>T​(p.Ser362Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,028 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.75

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 3 ACMG points.

• PM1: In a mutagenesis_site Abolishes binding to USP7. (size 0) in uniprot entity P53_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-7670625-T-A is Benign according to our data. Variant chr17-7670625-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458515.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.1084A>T	p.Ser362Cys	missense_variant	10/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1084A>T	p.Ser362Cys	missense_variant	10/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250058 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461028 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726828

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2021

This sequence change replaces serine with cysteine at codon 362 of the TP53 protein (p.Ser362Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 458515). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Benign:1

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 GRCh37:17:7573943:T>A was assigned evidence codes ['BS3_Moderate', 'BP4'] and an overall classification of Likely Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	.;.;.;D;.;D;.;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;.;.;.;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.8	.;.;.;L;.;L;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.36	.;.;.;N;.;N;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.21	.;.;.;T;.;T;.;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T
Polyphen		0.99	.;.;.;D;.;D;.;.
Vest4		0.47
MutPred		0.28		.;.;.;Loss of phosphorylation at S362 (P = 0.0047);.;Loss of phosphorylation at S362 (P = 0.0047);.;.;
MVP		0.87
MPC		0.33
ClinPred		0.51	D
GERP RS		5.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.3
Varity_R		0.32
gMVP		0.37

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: rs1287887419; hg19: chr17-7573943;