17-7673728-C-T

Variant names:

• chr17-7673728-C-T
• rs201744589
• NM_000546.6:c.892G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS3 BS2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000546.6 :c.892G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 298 (p.Gly298Lys). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; SCV000184859, SCV000260657). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.199; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000483/MONDO:0018875/009

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Benign reviewed by expert panel U:8 B:4
• Conservation: PhyloP100: -0.746

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 Benign. Variant got -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.892G>A	p.Glu298Lys	missense_variant	Exon 8 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.892G>A	p.Glu298Lys	missense_variant	Exon 8 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251492 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152240 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Benign

Submissions summary: Uncertain:8 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1 Benign:2

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2024

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000546.6 :c.892G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 298 (p.Gly298Lys). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; SCV000184859, SCV000260657). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.199; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Moderate, BS3, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.0; 7/24/2024) -

Jul 20, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 298 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). Experimental studies have shown this variant to be functional in transcriptional transactivation and cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in individuals affected with gastric cancer and acute lymphocytic leukemia in the literature (PMID: 21747090, 31949278). In a large international case-control study, this variant was reported in 1/60465 cases breast cancer cases and 2/53459 controls (OR=0.442, 95%CI 0.04 to 4.876, p-value=0.603; PMID: 33471991). This variant has been identified in 3/251492 chromosomes 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. -

Li-Fraumeni syndrome 1 Uncertain:2

Apr 14, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not provided Uncertain:1 Benign:1

Mar 04, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Apr 25, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 15, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 298 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). Experimental studies have shown this variant to be functional in transcriptional transactivation and cell growth suppression assays (PMID: 12826609, 30224644). This variant has been reported in individuals affected with gastric cancer and acute lymphocytic leukemia in the literature (PMID: 21747090, 31949278). In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and 2/53459 controls (OR=0.442, 95%CI 0.04 to 4.876, p-value=0.603; PMID: 33471991). This variant has been identified in 3/251492 chromosomes 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

Feb 05, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TP53 c.892G>A (p.Glu298Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.892G>A has been reported in the literature in individuals affected with breast cancer, childhood acute lymphoblastic leukemia, or osteosarcoma (e.g. Mirabello_2015, Qian_2018, Sheng_2020). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. The variant has been reported to be functional based on overall transcription activity on eight different promoters as measured in yeast assays (Kato_2003) and results of growth suppression assays indicated no loss of function or dominant negative effect of this variant (Giacomelli_2018). ClinVar contains an entry for this variant (Variation ID: 141483). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Carcinoma of colon Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TP53 p.Glu298Lys variant has been identified in 2 of 530 proband chromosomes (frequency: 0.004) of individuals affected with leukemia (Hof 2011). The variant was also identified in the following databases: dbSNP (ID: rs201744589) as “With Uncertain significance allele”, ClinVar (reported 3x as likely benign and uncertain significance by Ambry Genetics, Invitae and Counsyl), Cosmic (2x recurrence, endometrium, haematopoietic, Sinonasal and nasal cavity tissues, as carcinoma and lymphoid neoplasm) and IARC TP53 Database (7x somatic, 1x germline). The variant was not identified in Clinvitae, LOVD 3.0, UMD TP53 Mutation Database, and Database of germline p53 mutations. The variant was identified in control databases in 3 of 246268 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 2 of 33582 chromosomes (freq: 0.00006), and South Asian in 1 of 30782 chromosomes (freq: 0.00003). It was not observed in the African, Other, European Non-Finnish, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Glu298Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TP53 p.Glu298Lys variant has been identified in 2 of 530 proband chromosomes (frequency: 0.004) of individuals affected with leukemia (Hof 2011). The variant was also identified in the following databases: dbSNP (ID: rs201744589) as “With Uncertain significance allele”, ClinVar (reported 3x as likely benign and uncertain significance by Ambry Genetics, Invitae and Counsyl), Cosmic (2x recurrence, endometrium, haematopoietic, Sinonasal and nasal cavity tissues, as carcinoma and lymphoid neoplasm) and IARC TP53 Database (7x somatic, 1x germline). The variant was not identified in Clinvitae, LOVD 3.0, UMD TP53 Mutation Database, and Database of germline p53 mutations. The variant was identified in control databases in 3 of 246268 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 2 of 33582 chromosomes (freq: 0.00006), and South Asian in 1 of 30782 chromosomes (freq: 0.00003). It was not observed in the African, Other, European Non-Finnish, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Glu298Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	5.0
DANN	Benign	0.93
DEOGEN2	Benign	0.0078	T;.;.;.;.;T;T;.;T;.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.064	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.8	.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.37	N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL	Benign	0.29
Sift	Benign	0.093	T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T
Sift4G	Benign	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0020, 0.0060, 0.0010	.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.
Vest4		0.17
MVP		0.84
MPC		0.069
ClinPred		0.034	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.42

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: rs201744589; hg19: chr17-7577046; COSMIC: COSV53353479; COSMIC: COSV53353479;