17-7676050-A-G

Position:

chr17-7676050-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BS2BP4BS3_SupportingBS1

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.319T>C variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 107 (p.Tyr107His). 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 contributor: ClinVar SCV: SCV000172807.10). The filtering allele frequency is 0.0007936 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function. (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0202 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: BS1, BS2, BS3_supporting, BP4 (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000104/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:13

Conservation

PhyloP100: 2.49

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

BS1

BS2

BS3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.319T>C	p.Tyr107His	missense_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.319T>C	p.Tyr107His	missense_variant	4/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251350

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.000145

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000336

AC:

AN:

1460194

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726374

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.000134

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:

0.00

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000269

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 05, 2024	The NM_000546.6: c.319T>C variant in TP53 is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 107 (p.Tyr107His). 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 contributor: ClinVar SCV: SCV000172807.10). The filtering allele frequency is 0.0007936 in the African/African American population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function. (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.0202 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: BS1, BS2, BS3_supporting, BP4 (Bayesian Points: -10; VCEP specifications version 2.0; 7/24/2024). -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 16, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	May 20, 2020	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 08, 2021	- -

Li-Fraumeni syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 11, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 22, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2020	Variant summary: TP53 c.319T>C (p.Tyr107His) results in a conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Functional studies based on the overall transcriptional activity in yeast assays classified this variant as partially functional (Kato_2003). The variant allele was found at a frequency of 0.00012 in 282734 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, this variant was observed in old females, older than age 70 years who have never had cancer (FLOSSIES database). This variant has been reported in cancer patients without strong evidence for causality. Eight ClinVar submitters, including one expert panel (ClinGen TP53 Variant Curation Expert Panel, benign), (evaluation after 2014) cite the variant as uncertain significance (1x), likely benign (6x) and benign (1x). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 24, 2018	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	This variant is associated with the following publications: (PMID: 15073856, 24729566, 21373875, 26580448, 26206375, 27626311, 24797764, 28056804, 25896519, 28861920, 29979965, 30352134, 33300245) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 02, 2022	- -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 25, 2023

- -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 16, 2022

- -

TP53-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;.;D;.;.;.;.;.;.;D;.;.;T;T;.

Eigen

Benign

0.084

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.91

D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.12

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

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

1.7

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.63

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

REVEL

Uncertain

0.57

Sift

Benign

0.55

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

Sift4G

Benign

0.60

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

Polyphen

0.081

B;.;.;B;.;P;D;P;.;.;B;.;.;D;.;.

Vest4

0.23

MVP

0.89

MPC

1.9

ClinPred

0.099

GERP RS

4.8

Varity_R

0.41

gMVP

0.73

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