rs17881470

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS3BS2BP4

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.1096T>G variant in TP53 is a missense variant predicted to cause substitution of serine by alanine at amino acid 366 (p.Ser366Ala). This variant has been observed in at least 8 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, Internal lab contributors: SCV000214696.6). 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 = 0.1186; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 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). 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, BS3, BP4. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000036/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:11O:1

Conservation

PhyloP100: 0.669

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

BS2

BS3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.1096T>G	p.Ser366Ala	missense_variant	10/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.1096T>G	p.Ser366Ala	missense_variant	10/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

249484

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

134958

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.000232

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:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000699

AC:

102

AN:

1459402

Hom.:

Cov.:

AF XY:

0.0000744

AC XY:

AN XY:

726084

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000202

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:

0.0000703

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2019	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	curation	Sema4, Sema4	Mar 13, 2021	- -

Li-Fraumeni syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Sep 16, 2019	This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.1096T>G; p.Ser366Ala meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2020	This variant is associated with the following publications: (PMID: 24728327, 18511570, 12672316, 29467486, 19416725, 31422574, 21343334, 17606709, 19933256, 28861920, 15659650, 24729566, 24256616, 25503501, 30352134, 29844874, 31016814, 30840781, 33300245) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 06, 2021	- -

not specified

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2021	Variant summary: TP53 c.1096T>G (p.Ser366Ala) 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 6e-05 in 249484 control chromosomes, predominantly at a frequency of 0.00023 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096T>G has been reported in the literature in individuals affected with Li-Fraumeni Syndrome, breast- and bladder cancer, without strong evidence for causality (e.g. Monti_2007, Lalloo_2006, Bougeard_2008, Maxwell_ 2014); however, it was also found in healthy- or cancer-free controls as a secondary finding (e.g. Bodian_2014, de Andrade_2017, Kraemer_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (TP53 c.742C>T, p.Arg248Trp), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (e.g. Monti_2011, Shinmen_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=1)/likely benign (n=5). Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Aug 25, 2020

- -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The TP53 p.Ser366Ala variant was identified in 2 of 1112 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and was present in 3 of 1362 control chromosomes (frequency: 0.002) from healthy individuals (Lalloo 2006, Maxwell 2014, Bodian 2014). The variant was also identified in dbSNP (ID: rs17881470 as With Uncertain significance allele), ClinVar (Likely benign, reviewed by expert panel. Classified as LB by ClinGen, GeneDx, Ambry, Invitae, Color. Classified as B by Mendelics), Cosmic (previously reported in Acute lymphoblastic leukemia and Squamous cell carcinoma), LOVD 3.0 (as probably does not affect function), IARC TP53 Database, and UMD TP53 Mutation Database. Â¬â€ The variant was identified in control databases in 15 of 249484 chromosomes (0 homozygous) at a frequency of 0.00006012, and was observed at the highest frequency in the Latino population in 8 of 34410 chromosomes (freq: 0.0002325) (Genome Aggregation Database March 6, 2019, v2.1.1) The p.Ser366 residue is conserved in mammals, though 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 only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Ser366Ala variant was found to have a mean residual transactivation activity of a luciferase reporter gene at 101% relative to the wild type allele and was classified as a partial deficiency allele (Monti 2011). Another study showed that phosphorylation of Ser366 was markedly reduced in CHEK2-knockdown cells and that phosphorylation of Ser366 is activated by irradiation-induced DNA damage (Ou 2005). The phosphorylation of at least one but not all of three residues in p53, including S366, is essential for p53 regulation by some 14-3-3 isoforms (Rajagopalan 2010). Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4) (ClinGen ClinVar submission, SCV001142528.1). Â¬â€ In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

TP53-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Squamous cell carcinoma of the head and neck

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

.;.;.;T;.;T;.;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.47

T;T;.;.;.;T;T;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.41

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.4

.;.;.;L;.;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.33

.;.;.;N;.;N;.;.

REVEL

Uncertain

0.58

Sift

Benign

0.25

.;.;.;T;.;T;.;.

Sift4G

Benign

0.72

T;T;T;T;T;T;T;T

Polyphen

0.0010

.;.;.;B;.;B;.;.

Vest4

0.60

MutPred

0.16

.;.;.;Loss of phosphorylation at S366 (P = 0.0028);.;Loss of phosphorylation at S366 (P = 0.0028);.;.;

MVP

0.97

MPC

0.054

ClinPred

0.026

GERP RS

1.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.074

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over