Submissions for variant NM_024426.6(WT1):c.760C>T (p.Pro254Ser)

gnomAD frequency: 0.00022  dbSNP: rs2234584

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081231	SCV000290759	benign	Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000122310	SCV000540678	uncertain significance	not specified	2017-01-25	criteria provided, single submitter	clinical testing	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?).
Illumina Laboratory Services, Illumina	RCV001107940	SCV001265128	likely benign	Wilms tumor 1	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001107941	SCV001265129	benign	Meacham syndrome	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001107942	SCV001265130	likely benign	Nephrotic syndrome, type 4	2017-04-27	criteria provided, single submitter	clinical testing	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.
Genetic Services Laboratory, University of Chicago	RCV000122310	SCV002071507	uncertain significance	not specified	2020-10-01	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000782221	SCV002499792	likely benign	not provided	2024-03-08	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Sema4, Sema4	RCV002255305	SCV002530553	likely benign	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	curation
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV002284191	SCV002573586	uncertain significance	Microscopic hematuria	2022-02-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000782221	SCV003916708	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	WT1: PM5:Supporting, PS4:Supporting, BP4, BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122310	SCV004222986	likely benign	not specified	2025-01-10	criteria provided, single submitter	clinical testing	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 0.00052 in 1461804 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 55.97 fold of the estimated maximal expected allele frequency for a pathogenic variant in WT1 causing Wilms Tumor, Type 1 phenotype (9.4e-06). c.760C>T has been reported in the literature in individuals affected with Wilms Tumor, amongts other phenotypes (ie: Schumacher_1997, etc). These report(s) 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. The following publication has been ascertained in the context of this evaluation (PMID: 9108089). ClinVar contains an entry for this variant (Variation ID: 135453). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV003588578	SCV004360959	likely benign	Nephroblastoma	2022-09-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004965276	SCV005533816	benign	Inborn genetic diseases	2024-09-11	criteria provided, single submitter	clinical testing	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.
ITMI	RCV000122310	SCV000086540	not provided	not specified	2013-09-19	no assertion provided	reference population
Gharavi Laboratory, Columbia University	RCV000782221	SCV000920708	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000782221	SCV001798259	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000782221	SCV001975371	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551194	SCV004774787	likely benign	WT1-related disorder	2020-10-15	no assertion criteria provided	clinical testing	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).