17-7676262-G-T

Position:

• chr17-7676262-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM2_Supporting BS2 BP4 BS3

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.107C>A variant in TP53 is a missense variant predicted to cause substitution of proline by glutamine at amino acid 36 (p.Pro36Gln). This variant has been observed in 4-7 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_Moderate; Internal lab contributor: Invitae). 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 = -0.07; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. Although SpliceAI predicts a weak potential splice effect, expert review suggests that there is no actual impact on the native site, and the variant is therefore considered to have no impact on splicing (BP4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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_Moderate BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -7; VCEP specifications version 2.0; 9/6/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000031/MONDO:0007903/009

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Benign reviewed by expert panel U:5 B:2
• Conservation: PhyloP100: -0.119

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• 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	c.107C>A	p.Pro36Gln	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	c.107C>A	p.Pro36Gln	missense_variant	4/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 31

ClinVar

Significance: Benign

Submissions summary: Uncertain:5 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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	Jul 25, 2017	- -

Li-Fraumeni syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 36 of the TP53 protein (p.Pro36Gln). 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: 141597). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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. -
Benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Sep 06, 2024	The NM_000546.6: c.107C>A variant in TP53 is a missense variant predicted to cause substitution of proline by glutamine at amino acid 36 (p.Pro36Gln). This variant has been observed in 4-7 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_Moderate; Internal lab contributor: Invitae). 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 = -0.07; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. Although SpliceAI predicts a weak potential splice effect, expert review suggests that there is no actual impact on the native site, and the variant is therefore considered to have no impact on splicing (BP4_Moderate). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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_Moderate BS3, BP4_Moderate, PM2_Supporting. (Bayesian Points: -7; VCEP specifications version 2.0; 9/6/2024) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 19, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 10, 2019	This missense variant replaces proline with glutamine at codon 36 of the TP53 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Yeast transactivation assays reported the variant protein to be functional (PMID 12826609 and the International Agency for Research on Cancer). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 27, 2014

This variant is denoted TP53 c.107C>A at the cDNA level, p.Pro36Gln (P36Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). TP53 Pro36Gln has been observed as a somatic mutation in hematopoietic malignancy and reported to demonstrate functional transactivation activity similar to wild type in a yeast assay (IARC TP53 Database, Shiraishi 2004). TP53 Pro36Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Pro36Gln occurs at a position that is variable across species and is located in the transcription activation domain and region of interaction with HRMT1L2 (UniProt). Multiple in silico models predict formation of a new, cryptic splice acceptor site of equivalent strength as the natural splice acceptor site. In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether TP53 Pro36Gln is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	3.0
DANN	Benign	0.54
DEOGEN2	Benign	0.0079	T;T;T;.;.;.;T;.;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.85	T;T;.;T;T;.;T;T;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.1	.;.;L;L;L;L;L;.;.;.;.
PROVEAN	Benign	-0.15	N;N;N;.;N;N;N;.;N;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.11	T;T;T;.;T;T;T;.;T;.;T
Sift4G	Benign	0.56	T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.73	P;.;P;B;P;B;P;.;P;.;.
Vest4		0.19
MutPred		0.20		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);
MVP		0.87
MPC		0.69
ClinPred		0.11	T
GERP RS		-0.84
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.23
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781866; hg19: chr17-7579580;