rs35993958

Positions:

• chr17-7670630-C-A
• chr17-7670630-C-G
• chr17-7670630-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000546.6(TP53):​c.1079G>T​(p.Gly360Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. G360A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.0240

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_benign. Variant got -5 ACMG points.

• PM1: In a region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 512 pathogenic changes around while only 124 benign (81%) in NM_000546.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.09957361).
• BP6: Variant 17-7670630-C-A is Benign according to our data. Variant chr17-7670630-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142552.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.1079G>T	p.Gly360Val	missense_variant	10/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.1079G>T	p.Gly360Val	missense_variant	10/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250440 Hom.: 0 AF XY: 0.0000664 AC XY: 9 AN XY: 135450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461598 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 21, 2023	Variant summary: TP53 c.1079G>T (p.Gly360Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 1613746 control chromosomes. The observed variant frequency is above the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. c.1079G>T has been reported in the literature in individuals affected with neuroblastoma (Kudo_2018) without evidence for causality or segregation with diease. This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Co-occurrences with another pathogenic variant have been reported (ALK c.3824G>A, p.Arg1275Gln, Kudo_2018), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function suggesting it is functional (Said_2016, Kato_2003). The following publications have been ascertained in the context of this evaluation (PMID: 27297285, 12826609, 35352025, 30350464). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=7) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2015	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 13, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	This variant is associated with the following publications: (PMID: 20597068, 30287823, 28945843, 25256751, 8577720, 25503501, 27297285, 30840781, 12826609, 31740566, 31320002, 14559903) -

Li-Fraumeni syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	2.0
DANN	Benign	0.27
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.53	T;T;.;.;.;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T
Polyphen		0.012	.;.;.;B;.;B;.;.
Vest4		0.36
MutPred		0.15		.;.;.;Gain of MoRF binding (P = 0.0862);.;Gain of MoRF binding (P = 0.0862);.;.;
MVP		0.76
MPC		0.13
ClinPred		0.019	T
GERP RS		0.93
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.057
gMVP		0.34

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: rs35993958; hg19: chr17-7573948;