rs17881470

Variant names:

• chr17-7670613-A-C
• rs17881470
• NM_000546.6:c.1096T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-7670613-A-C
• chr17-7670613-A-G
• chr17-7670613-A-T

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.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
• Clinical Significance: Benign reviewed by expert panel U:1 B:12 O:1
• Conservation: PhyloP100: 0.669

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.1096T>G	p.Ser366Ala	missense_variant	Exon 10 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1096T>G	p.Ser366Ala	missense_variant	Exon 10 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152120 Hom.: 0 Cov.: 32

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: 15 AN: 249484 Hom.: 0 AF XY: 0.0000815 AC XY: 11 AN XY: 134958

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.: 0 Cov.: 30 AF XY: 0.0000744 AC XY: 54 AN XY: 726084

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: 7 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74444

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.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:4

Dec 29, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2019

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. -

Mar 13, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 16, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS2, BS3, BP4 c.1096T>G, located in exon 10 of the TP53 gene, is predicted to result in the substitution of serine by alanine at codon 366, p.(Ser366Ala). This variant is found in 14/266783 alleles at a frequency of 0.005% in the gnomAD v2.1.1 database, non-cancer dataset. Computational tools for this variant suggest no significant impact on splicing and does not affect the protein function (BayesDel: 0.12) (BP4). This variant is found in a clinically calibrated functional assay, showing no impact on protein function (PMID: 12826609) (BS3). It has been observed in at least 8 heterozygous unrelated healthy females, older than 60 years (BS2). This variant has been reported in the ClinVar database (1x benign, 8x likely benign, 1x uncertain significance) and in LOVD (1x likely benign). Furthermore, it has been recently classified by the ClinGen TP53 Variant Curation Expert Panel as benign. Based on currently available information, the variant c.1096T>G should be considered a benign variant according to ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.2.0. -

Li-Fraumeni syndrome Benign:2

Feb 03, 2025

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.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) -

not provided Benign:2

Dec 06, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Apr 25, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Breast and/or ovarian cancer Uncertain:1

Aug 25, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.  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).  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

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	.;.;.;T;.;T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.47	T;T;.;.;.;T;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.4	.;.;.;L;.;L;.;.
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs17881470; hg19: chr17-7573931; COSMIC: COSV52875421; COSMIC: COSV52875421;