chr17-7675119-G-T

Position:

• chr17-7675119-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000546.6(TP53):​c.493C>A​(p.Gln165Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.28

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 2 ACMG points.

• PM1: In a strand (size 9) in uniprot entity P53_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1434657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.493C>A	p.Gln165Lys	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.493C>A	p.Gln165Lys	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 20, 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, 29979965, 30224644). 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: 482232). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 165 of the TP53 protein (p.Gln165Lys). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 14, 2024	This missense variant replaces glutamine with lysine at codon 165 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant behave like wild-type TP53 in yeast transcriptional transactivation assays and human cell growth suppression and proliveration assays (PMID: 12826609, 29979965, 30224644). This variant has been reported in individuals affected with breast cancer (PMID: 30287823, 33471991). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 11, 2024

Variant summary: TP53 c.493C>A (p.Gln165Lys) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 31374 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. One large case-control study evaluating breast cancer genetic risk also reported this variant was present in one case but not in the control cohort (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function by high-throuput in vitro assays. These results showed no damaging effect of this variant (Kotler_2018). The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 29979965). ClinVar contains an entry for this variant (Variation ID: 482232). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2016

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	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	15
DANN	Benign	0.22
DEOGEN2	Benign	0.29	T;T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	-2.3	.;.;.;.;.;.;.;.;.;N;.;N;N;N;.;.;N;.;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	3.1	N;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T;T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.0	B;.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B;.
Vest4		0.26
MutPred		0.58		Gain of methylation at Q165 (P = 0.0172);Gain of methylation at Q165 (P = 0.0172);.;.;.;.;.;.;.;Gain of methylation at Q165 (P = 0.0172);.;Gain of methylation at Q165 (P = 0.0172);Gain of methylation at Q165 (P = 0.0172);Gain of methylation at Q165 (P = 0.0172);.;.;Gain of methylation at Q165 (P = 0.0172);.;.;.;.;Gain of methylation at Q165 (P = 0.0172);
MVP		0.76
MPC		0.82
ClinPred		0.11	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.32

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: rs730882001; hg19: chr17-7578437;