rs2234584

chr11-32428521-G-Achr11-32428521-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_024426.6(WT1):c.760C>T(p.Pro254Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000513 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P254L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: WT1 NM_024426.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:11 O:1
• Conservation: PhyloP100: 6.42

Genes affected

WT1 (HGNC:12796): (WT1 transcription factor) This gene encodes a transcription factor that contains four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a small subset of patients with Wilms tumor. This gene exhibits complex tissue-specific and polymorphic imprinting pattern, with biallelic, and monoallelic expression from the maternal and paternal alleles in different tissues. Multiple transcript variants have been described. In several variants, there is evidence for the use of a non-AUG (CUG) translation initiation codon upstream of, and in-frame with the first AUG. Authors of PMID:7926762 also provide evidence that WT1 mRNA undergoes RNA editing in human and rat, and that this process is tissue-restricted and developmentally regulated. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056760073).
• BS2: High AC in GnomAd at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WT1	NM_024426.6	c.760C>T	p.Pro254Ser	missense_variant	2/10	ENST00000452863.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WT1	ENST00000452863.10	c.760C>T	p.Pro254Ser	missense_variant	2/10	1	NM_024426.6

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000390 AC: 98 AN: 251132 Hom.: 0 AF XY: 0.000412 AC XY: 56 AN XY: 135842

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000525 AC: 767 AN: 1461804 Hom.: 1 Cov.: 33 AF XY: 0.000509 AC XY: 370 AN XY: 727212

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000627

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74482

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:11 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2023	Identified in patients with steroid-resistant nephrotic syndrome (SRNS), Wilms tumor, or variations of sex characteristics, but also in individuals without any WT1-related disorder (Schumacher et al., 1997; Kohler et al., 2004; Little et al., 2004; Kohler et al., 2011; Bodian et al., 2014; Lehnhardt et al., 2015; He et al., 2016; Sen et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.541C>T (p.P181S); This variant is associated with the following publications: (PMID: 24728327, 26934580, 21508141, 26489027, 26332594, 9108089, 15483024, 15191353, 25818337, 8019557, 28873162, 27288520, 27930734, 26343386, 25451826, 28780565, 19221039, 8486616) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	WT1: PM5:Supporting, PS4:Supporting, BP4, BS1 -

not specified Uncertain:2 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 01, 2020	DNA sequence analysis of the WT1 gene demonstrated a sequence change, c.760C>T, in exon 2 that results in an amino acid change, p.Pro254Ser. This sequence change has been described in the gnomAD database with a frequency of 0.063% in the European sub-population (dbSNP rs2234584). The p.Pro254Ser change has been identified in one individual with Wilm's tumor and another individual with 46,XY disorder of sexual development (PMIDs: 9108089, 21508141). The p.Pro254Ser change affects a moderately conserved amino acid residue located in a domain of the WT1 protein that is known to be functional. The p.Pro254Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro254Ser change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	Variant summary: WT1 c.760C>T (p.Pro254Ser) results in a non-conservative amino acid change in 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 0.00039 in 251132 control chromosomes. The observed variant frequency is approximately 41.62 fold of the estimated maximal expected allele frequency for a pathogenic variant in WT1 causing Wilms Tumor, Type 1 phenotype (9.4e-06), strongly suggesting that the variant is benign. c.760C>T has been reported in the literature in individuals affected with Wilms Tumor, amongts other phenotypes (ie: Schumacher_1997, etc). These reports do not provide unequivocal conclusions about association of the variant with Wilms Tumor, Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: five submitted the variant as VUS while five submitted the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified this year. The variant has been reported in 4 papers: 1 patient with wilms tumor but no second somatic mutation, 1 healthy indvidual, 1 with abnormal sex development, and one with ureteropelvic junction obstruction in which it was predicted to be VUS. It has been seen in 40/66282 alleles in ExAC (0.06%) (too high for disease/gene contribution?). -

Microscopic hematuria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Feb 15, 2022

- -

11p partial monosomy syndrome;C0950121:Drash syndrome;C0950122:Frasier syndrome;CN033288:Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Nephroblastoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 16, 2022

- -

Meacham syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Nephrotic syndrome, type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

WT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 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). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Nov 05, 2021

- -

Wilms tumor 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	23
Dann	Pathogenic	1.0
Eigen	Benign	-0.056
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.;D;.;.;.;.;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.057	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	N;N;N;N;N;.;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.14	T;T;T;T;T;.;.;.
Sift4G	Benign	0.80	T;T;T;T;T;.;.;.
Polyphen		0.0040	B;.;.;.;.;.;.;.
Vest4		0.82
MVP		0.71
ClinPred		0.056	T
GERP RS		5.6
gMVP		0.26

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: rs2234584; hg19: chr11-32450067; COSMIC: COSV60071168;