NM_024426.6(WT1):c.973G>A (p.Ala325Thr) AND Wilms tumor 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 26, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001104526.7

Allele description [Variation Report for NM_024426.6(WT1):c.973G>A (p.Ala325Thr)]

NM_024426.6(WT1):c.973G>A (p.Ala325Thr)

Gene:

WT1:WT1 transcription factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p13

Genomic location:

Preferred name:

NM_024426.6(WT1):c.973G>A (p.Ala325Thr)

HGVS:

NC_000011.10:g.32416533C>T
NG_009272.1:g.24009G>A
NM_000378.6:c.965+1044G>A
NM_001198551.2:c.322G>A
NM_001198552.2:c.314+1044G>A
NM_001407044.1:c.973G>A
NM_001407046.1:c.973G>A
NM_001407047.1:c.850G>A
NM_001407051.1:c.211G>A
NM_024424.5:c.973G>A
NM_024426.6:c.973G>AMANE SELECT
NP_001185480.1:p.Ala108Thr
NP_001185480.1:p.Ala108Thr
NP_001393973.1:p.Ala325Thr
NP_001393975.1:p.Ala325Thr
NP_001393976.1:p.Ala284Thr
NP_001393980.1:p.Ala71Thr
NP_077742.3:p.Ala325Thr
NP_077744.3:p.Ala320Thr
NP_077744.4:p.Ala325Thr
LRG_525t1:c.958G>A
LRG_525t2:c.322G>A
LRG_525:g.24009G>A
LRG_525p1:p.Ala320Thr
LRG_525p2:p.Ala108Thr
NC_000011.9:g.32438079C>T
NC_000011.9:g.32438079C>T
NM_001198551.1:c.322G>A
NM_024426.3:c.958G>A
NM_024426.4:c.958G>A
NR_160306.1:n.1305G>A

Protein change:

A108T

Links:

dbSNP: rs1712081462

NCBI 1000 Genomes Browser:

rs1712081462

Molecular consequence:

NM_000378.6:c.965+1044G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001198552.2:c.314+1044G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001198551.2:c.322G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407044.1:c.973G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407046.1:c.973G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407047.1:c.850G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407051.1:c.211G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024424.5:c.973G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024426.6:c.973G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_160306.1:n.1305G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Wilms tumor 1 (WT1)
Synonyms:: Wilms tumor, somatic
Identifiers:: MONDO: MONDO:0008679; MedGen: CN033288; Orphanet: 654; OMIM: 194070

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HAAS signaling domain-containing protein [Gluconobacter albidus]
HAAS signaling domain-containing protein [Gluconobacter albidus]
gi|1720562215|ref|WP_145995610.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001261399	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV004832836	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 26, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001261399

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV004832836

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 26, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001261399.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004832836.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces alanine with threonine at codon 320 of the WT1 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 WT1-related disorders 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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