chr17-7676040-C-T

Position:

chr17-7676040-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BS3_SupportingBP4BS2_Supporting

This summary comes from the ClinGen Evidence Repository: This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show a partially functional variant 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_Supporting; PMID:12826609, 30224644). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor.) In summary, TP53 c.329G>A (p.Arg110His) 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, BS3_Supporting, BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000123/MONDO:0018875/009

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:9B:5O:1

Conservation

PhyloP100: 0.604

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 Likely_benign. Variant got -3 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/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.329G>A	p.Arg110His	missense_variant	4/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.329G>A	p.Arg110His	missense_variant	4/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251284

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000630

AC:

AN:

1460088

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726324

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000710

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:9Benign:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 25, 2022	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	Jul 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 18, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 09, 2018	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies are inconclusive: partially functional transactivation; growth suppression and apoptotic activities comparable to wild-type (Bergamaschi 2003, Kato 2003, Kotler 2018); Observed in individuals with breast cancer (Rath 2013, Tung 2016, Hauke 2018); This variant is associated with the following publications: (PMID: 16061860, 24728327, 24113472, 17062677, 26976419, 28446639, 21512767, 12826609, 22356895, 22228431, 26206375, 29979965, 14612556, 23243274, 23580068, 29522266, 21552135, 12726864, 30352134, 31016814, 30840781) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 10, 2020	The TP53 c.329G>A; p.Arg110His variant (rs11540654) has been previously reported in at least two individuals with a personal history of breast cancer who tested negative for pathogenic variation in numerous genes associated with hereditary breast cancer, including BRCA1 and BRCA2, though the identified p.Arg110His variant was not definitively determined to be causative(Rath 2013 and Hauke 2018). Early promoter transactivation studies indicate this variant results in a partially active TP53 protein (Kato 2003; IARC Database). However, subsequent functional analyses have demonstrated that this variant does not confer a significant growth advantage in cell culture models of TP53-mediated cellular proliferation (Bergamaschi 2003, Giacomelli 2018, Kotler 2018). These conclusions of a neutral effect on protein function are in line with computational models demonstrating that the arginine at codon 110 is weakly conserved (Alamut v.2.11; with several related species harboring a histidine at this position), and that the substituted histidine is a small physiochemical change from arginine. The p.Arg110His variant is found in the general population with an overall allele frequency of 0.005% (13/282,662 alleles) in the Genome Aggregation Database, and was found in an individual included in a healthy, unselected population (Bodian 2014). Post hoc analysis of these frequency estimates, in addition to observations from other cancer cohorts, has resulted in discrepant conclusions regarding pathogenicity. One study has suggested that this variant is likely to be pathogenic based on population frequency, though the authors specified that they established separate nonclinical classification criteria for research purposes (Andrade 2019), whereas two studies (one in direct critical response to Andrade et al) have concluded that this variant is more likely to be benign (Evans 2019 and Fortuno 2019). In reflection of the many conflicting pieces of information regarding the p.Arg110His variant, it should be noted that an FDA-recognized expert panel has concluded this variant is likely to be benign (ClinVar Variation ID: 127808). Based on the available information, we consider the clinical significance of this variant to be uncertain at this time. REFERENCES Andrade KC et al. Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis Hum Mutat. 2019 Jan;40(1):97-105. Bergamaschi D et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell. 2003 Apr;3(4):387-402. Bodian et al., Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. PLoS One. 2014 Apr 11;9(4):e94554. Evans et al., Concern regarding classification of germline TP53 variants as likely pathogenic. Hum Mutat. 2019 Jun;40(6):828-831. Fortuno et al., A quantitative model to predict pathogenicity of missense variants in the TP53 gene. Hum Mutat. 2019 Jun;40(6):788-800. Giacomelli AO et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet. 2018 Oct;50(10):1381-1387. Hauke J et al. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med. 2018 Apr;7(4):1349-1358. Kato S et al. Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Kotler E et al. A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. Mol Cell. 2018 Jul 5;71(1):178-190.e8. Rath et al., Prevalence of germline TP53 mutations in HER2+ breast cancer patients. Breast Cancer Res Treat. 2013 May;139(1):193-8. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 16, 2019	- -

Li-Fraumeni syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 12, 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	Jan 27, 2016	- -

not specified

Uncertain:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 20, 2022	Variant summary: TP53 c.329G>A (p.Arg110His) results in a non-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. The variant allele was found at a frequency of 4.8e-05 in 251284 control chromosomes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), suggesting that the variant is benign. c.329G>A has been reported in the literature in individuals in individuals with leukemia (Jeromin_2014, Winter_2021), head and neck cancer (Bergamaschi _2003, Vivenza_2012) and breast cancer (Boyault_2011, Rath_2013, Silwat-Pandt_2014, Tung_2016). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Several publications report mixed mixed results on the impact of the variant on protein function. These reports indicate no impact on expression, but transactivation experiments have ranged in their assessments from functionally abnormal to indistinguishable from wild-type (Doffe_2020, Raad_2021). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories and one expert panel reported the variant with conflicting assessments (7 classified it as VUS, 2 as likely benign). Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Li-Fraumeni syndrome

Benign:2

Likely benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 11, 2020	This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show a partially functional variant 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_Supporting; PMID: 12826609, 30224644). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor.) In summary, TP53 c.329G>A (p.Arg110His) 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, BS3_Supporting, BS2_Supporting. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The TP53 p.Arg110His variant was identified in 1 of 14548 proband chromosomes (frequency: 0.00007) from individuals or families with breast cancer or HER2+ breast cancer and was present in 3 of 23844 control chromosomes (frequency: 0.0001) from healthy individuals (Momozawa 2018, Rath 2014, Bodian 2014). The variant was also identified in dbSNP (ID: rs11540654) as "With Likely pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and three other submitters), and in LOVD 3.0 (2X). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 13 of 277020 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24008 chromosomes (freq: 0.00004), Latino in 3 of 34416 chromosomes (freq: 0.00009), European in 6 of 126568 chromosomes (freq: 0.00005), and East Asian in 3 of 18862 chromosomes (freq: 0.0002); it was not observed in the Other, Ashkenazi Jewish, Finnish, or South Asian populations. One study found that this variant had a similar effect on the modulation of cytotoxicity as compared to a control, suggesting a non-pathogenic role for this variant (Bergamaschi 2003). The p.Arg110 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,) 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. -

TP53-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

The TP53 c.329G>A variant is predicted to result in the amino acid substitution p.Arg110His. This variant has been reported in individuals with breast cancer (Rath et al. 2013. PubMed ID: 23580068; Tung et al. 2016. PubMed ID: 26976419, Table A2; Hauke et al. 2018. PubMed ID: 29522266, Table S2); however, no evidence was provided to support its pathogenicity. It was predicted to be likely benign using a quantitative model to predict pathogenicity of missense variants (Fortuno et al. 2019. PubMed ID: 30840781, Table S1). Another study reported this variant as likely benign after case control comparisons, and functional analysis evidence (Evans et al. 2019. PubMed ID: 31016814). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. In ClinVar, laboratories classify it is a variant of uncertain significance, and the ClinGen TP53 Variant Curation Expert Panel classifies it as likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127808/). While we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.40

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

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.017

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.36

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

1.2

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

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.68

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

REVEL

Uncertain

0.59

Sift

Benign

0.30

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

Sift4G

Benign

0.19

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

Polyphen

0.054

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

Vest4

0.46

MVP

0.94

MPC

0.89

ClinPred

0.041

GERP RS

-0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.24

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