rs1800371

chr17-7676230-G-Achr17-7676230-G-Cchr17-7676230-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000546.6(TP53):c.139C>T(p.Pro47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00087 in 1,614,080 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P47R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:20 O:1
• Conservation: PhyloP100: -3.33

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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 16 uncertain in NM_000546.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0042043626).
• BP6: Variant 17-7676230-G-A is Benign according to our data. Variant chr17-7676230-G-A is described in ClinVar as [Benign]. Clinvar id is 43588.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00459 (698/152198) while in subpopulation AFR AF= 0.0161 (669/41510). AF 95% confidence interval is 0.0151. There are 8 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 699 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.139C>T	p.Pro47Ser	missense_variant	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.139C>T	p.Pro47Ser	missense_variant	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 699 AN: 152080 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

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: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00123 AC: 310 AN: 251372 Hom.: 1 AF XY: 0.000971 AC XY: 132 AN XY: 135876

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000483 AC: 706 AN: 1461882 Hom.: 6 Cov.: 59 AF XY: 0.000441 AC XY: 321 AN XY: 727244

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00459 AC: 698 AN: 152198 Hom.: 8 Cov.: 31 AF XY: 0.00441 AC XY: 328 AN XY: 74428

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00174 Hom.: 2

Bravo AF: 0.00556

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00171 AC: 208

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:20 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1 Benign:4 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 23, 2011	The Pro47Ser variant in TP53 is a common polymorphism in individuals with Africa n ancestry and has an observed minor allele frequency ranging from 2.2 - 6.7% in Yorubans (HapMap and 1000 Genomes; Felley-Bosco 1993). This polymorphism has a lso been observed in Brazilian and Kashmiri populations with gliomas, bladder an d colorectal cancer (Pinto 2008, Sameer 2010, Santos 2011). Despite the common nature of this polymorphism, there have been extensive functional studies sugges ting the Pro47Ser change has functional consequences and associated with increas ed cancer susceptibility; however, the data and consensus is variable (Olivier 2 010). The proline at position 47 lies adjacent to a functionally important prol ine-rich region (amino acids 64-92) and the adjacent serine at position 46 has b een reported to be an important phosphorylation site necessary for p53-dependent apoptotic activity (Pistritto 2007). Moreover, functional studies suggest the Pro47Ser variant has decreased activity to transactivate downstream apoptotic ef fector molecules (Li 2005; Whibley 2009). Proline at position 47 is poorly cons erved in vertebrate organisms and absent from more distantly related organisms, suggesting a benign role. The variant has never been reported in a family with Li Fraumeni syndrome. Although this variant is a common polymorphism, the clinic al significance of it, particuarly in the homozgyous state, cannot be determined at this time. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -

Li-Fraumeni syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 28, 2019	This variant has a minor allele frequency of 0.01645 (1.6%, 410/24,922 alleles) in the African subpopulation of the gnomAD cohort (BA1). The variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show 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 at least 105 60+ year old females without a cancer diagnosis (BS2; FLOSSIES database - https://whi.color.com). In summary, TP53 c.139C>T; p.Pro47Ser meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BA1, BP4, BS3, BS2. -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The TP53 c.139C>T (p.Pro47Ser) variant located in the transactivation domain involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a benign outcome for this substitution. his variant was found in 436/277308 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.016374 (393/24002). This frequency is about 412 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, case-control studies also show that this variant does not confer an associated cancer risk. Despite the common nature of this polymorphism, functional studies are inconclusive as to whether the variant has functional consequences. Some studies (Li_ 2005, Rigacci_2008, Jennis_ 2014 and Jennis_2016) have shown that this variant leads to functional impairment, while Wasserman_2015 indicates the variant has an additive affect, suggesting a notion that this variant is a functional polymorphism. The proline at position 47 lies adjacent to a functionally important proline-rich region (amino acids 64-92) and the adjacent serine at position 46 has been reported to be an important phosphorylation site necessary for p53-dependent apoptotic activity. A functional sudy published showed that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (ironmediated nonapoptotic cell death) and that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Based on these observations Jennis_2016 suggested that the S47 variant may contribute to increased cancer risk in individuals of African descent. However, multiple clinical diagnostic laboratories have cited the variant as Benign. Furthermore, the variant of interest has been found to co-occur with multiple pathogenic variants, PTEN c.406T>C (p.Cys136Arg) and BRCA1 c.213-12A>G and likely pathogenic MLH1 variant, c.1731+1G>T (2 individuals). Taken together, their is a discrepancy between the clinical observations (co-occurrence with other pathogenic/likely pathogenic variants, and large excess in the control cohort) and functional data, where a correlation between the measured property and the disease physiology has not been clearly established. Therefore, this variant is classified as "Benign". -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 15, 2021	- -

Li-Fraumeni syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Pathway Genomics	Oct 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 08, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 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

Jul 07, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 19, 2021

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The TP53 p.Pro47Ser variant was identified in 41 of 5182 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer, brain tumour, gliomas, bladder cancer or Lynch syndrome and was present in 6 of 2858 control chromosomes (frequency: 0.002) from healthy individuals (Alawadi 2011, Almeida 2009, Bodian 2014, Cock-Rada 2017, Pinto 2008, Sameer 2010, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs1800371) as ‚ With Uncertain significance, other allele‚Äù, ClinVar (as benign by GeneDx, Ambry Genetics, Pathway Genomics, EGL Genetic Diagnostics, Invitae, ARUP, Color Genomics, Integrated Genetics, and Mayo Clinic and as uncertain significance by Laboratory for Molecular Medicine), Cosmic (3x found in liver, endometrium and kidney cancer), LOVD 3.0 (1x), and in IARC TP53 (as neutral). The variant was not identified in the Database of germline p53 mutations. The variant was identified in control databases in 433 of 277106 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 393 of 24002 chromosomes (freq: 0.02), Other in 4 of 6464 chromosomes (freq: 0.001), Latino in 30 of 34412 chromosomes (freq: 0.001), European in 4 of 126662 chromosomes (freq: 0.00003), and South Asian in 2 of 30780 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, and Finnish populations. The p.Pro47 residue is not conserved in mammals and four out of five 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, HumanSpliceFinder) do not predict a difference in splicing. The Pro47Ser polymorphism has a significant influence on p53 function, by reducing phosphorylation on serine 46 and impairing p53 apoptotic and transcriptional functions (Olivier 2010, Li 2005) in mouse embryo fibroblasts (Basu 2016,). The functional study of the p53 transactivation domain aggregates in vitro showed aggregation propensity of the Pro47Ser mutated peptide have the same rate as the wild type (Rigacci 2008). In another study (Cock-Rada 2017) the variant was identified with a co-occurring pathogenic BRCA1 variant, suggesting the Pro47Ser variant may not have clinical significance. Association of Pro47Ser polymorphism was not observed in bladder (Santos 2011), gliomas (Pinto 2008), colorectal cancer (Sameer 2010), and breast cancer (Alawadi 2011, Sharma 2014). In addition, the meta-analysis of 11 case-control studies by Chandel (2013) concluded that published results seem to be driven by technical artifacts rather than justified biological effects. This systematic review and meta-analysis of genetic association studies shows that TP53 p.Pro47Ser is unlikely to be a major risk factor for different types of cancers and many diseases. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	0.021
Dann	Benign	0.43
DEOGEN2	Benign	0.0044	T;T;.;T;.;.;.;.;.;.;T;.;.;T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.74	T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.79	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.26	N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL	Uncertain	0.32
Sift	Benign	0.18	T;T;.;T;.;.;T;T;.;.;T;.;.;T;.;T
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.0050	B;.;.;B;.;B;B;B;.;.;B;.;.;B;.;.
Vest4		0.11
MVP		0.81
MPC		0.65
ClinPred		0.0047	T
GERP RS		-7.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800371; hg19: chr17-7579548; COSMIC: COSV53150763; COSMIC: COSV53150763;