rs1060501199

Positions:

• chr17-7673577-C-A
• chr17-7673577-C-G
• chr17-7673577-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_000546.6(TP53):​c.951G>T​(p.Gln317His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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. Q317K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.552

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 Uncertain_significance. Variant got 1 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19210356).
• BP6: Variant 17-7673577-C-A is Benign according to our data. Variant chr17-7673577-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406585.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.951G>T	p.Gln317His	missense_variant	9/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.951G>T	p.Gln317His	missense_variant	9/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

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

Invitae

May 30, 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 does not substantially affect TP53 function (PMID: 12826609). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 406585). This missense change has been observed in individual(s) with Balkan endemic nephropathy (PMID: 16487937). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 317 of the TP53 protein (p.Gln317His). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	9.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.11	T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.84, 0.89, 0.94	.;.;.;.;.;.;.;.;P;.;P;P;P;.;.;P;.;.;.
Vest4		0.17
MutPred		0.22		Gain of glycosylation at P316 (P = 0.0916);.;.;.;.;.;.;.;Gain of glycosylation at P316 (P = 0.0916);.;Gain of glycosylation at P316 (P = 0.0916);Gain of glycosylation at P316 (P = 0.0916);Gain of glycosylation at P316 (P = 0.0916);.;.;Gain of glycosylation at P316 (P = 0.0916);.;.;.;
MVP		0.93
MPC		0.28
ClinPred		0.68	D
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
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: rs1060501199; hg19: chr17-7576895;