17-7676154-G-T

Position:

• chr17-7676154-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. BP4 BS2_Supporting BS3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). ). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show [retained/supertransactivation] 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) Finally, this variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting, Invitae internal data). In summary, TP53 c.215C>A; p.Pro72His 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: PM2_supporting, BP4, BS3, BS2_supporting. PM2_Supporting should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000071/MONDO:0007903/009

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (1 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:2
• Conservation: PhyloP100: 1.44

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 Likely_benign. Variant got -5 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.215C>A	p.Pro72His	missense_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.215C>A	p.Pro72His	missense_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461570 Hom.: 1 Cov.: 80 AF XY: 0.0000165 AC XY: 12 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 26, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 15, 2021	This missense variant replaces proline with histidine at codon 72 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 10, 2022	- -

Li-Fraumeni syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 72 of the TP53 protein (p.Pro72His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 185120). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 28, 2023	This missense variant replaces proline with histidine at codon 72 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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 Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Apr 19, 2021

This variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). ). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show [retained/supertransactivation] 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) Finally, this variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting, Invitae internal data). In summary, TP53 c.215C>A; p.Pro72His 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: PM2_supporting, BP4, BS3, BS2_supporting. PM2_Supporting should not be considered conflicting evidence as variant otherwise meets criteria for Likely Benign classification. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.0088	T;T;.;D;.;.;.;.;.;.;D;.;.;T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.46	T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.14	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.049	D;T;.;D;.;.;D;D;.;.;D;.;.;T;.;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.99	D;.;.;P;.;P;P;P;.;.;P;.;.;B;.;.
Vest4		0.24
MutPred		0.21		Loss of catalytic residue at P71 (P = 0.0179);Loss of catalytic residue at P71 (P = 0.0179);.;Loss of catalytic residue at P71 (P = 0.0179);.;Loss of catalytic residue at P71 (P = 0.0179);Loss of catalytic residue at P71 (P = 0.0179);Loss of catalytic residue at P71 (P = 0.0179);.;.;Loss of catalytic residue at P71 (P = 0.0179);.;Loss of catalytic residue at P71 (P = 0.0179);Loss of catalytic residue at P71 (P = 0.0179);Loss of catalytic residue at P71 (P = 0.0179);Loss of catalytic residue at P71 (P = 0.0179);
MVP		0.89
MPC		1.1
ClinPred		0.12	T
GERP RS		1.9
Varity_R		0.14
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: rs1042522; hg19: chr17-7579472; COSMIC: COSV53098660; COSMIC: COSV53098660;