NM_001904.4(CTNNB1):c.122C>T (p.Thr41Ile) AND Desmoid disease, hereditary

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 10, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004562216.1

Allele description [Variation Report for NM_001904.4(CTNNB1):c.122C>T (p.Thr41Ile)]

NM_001904.4(CTNNB1):c.122C>T (p.Thr41Ile)

Genes:

LOC126806658:BRD4-independent group 4 enhancer GRCh37_chr3:41265899-41267098 [Gene]
CTNNB1:catenin beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.1

Genomic location:

Preferred name:

NM_001904.4(CTNNB1):c.122C>T (p.Thr41Ile)

HGVS:

NC_000003.12:g.41224634C>T
NG_013302.2:g.30184C>T
NM_001098209.2:c.122C>T
NM_001098210.2:c.122C>T
NM_001330729.2:c.101C>T
NM_001904.4:c.122C>TMANE SELECT
NP_001091679.1:p.Thr41Ile
NP_001091680.1:p.Thr41Ile
NP_001317658.1:p.Thr34Ile
NP_001895.1:p.Thr41Ile
LRG_1108t1:c.122C>T
LRG_1108:g.30184C>T
LRG_1108p1:p.Thr41Ile
NC_000003.11:g.41266125C>T
P35222:p.Thr41Ile

Protein change:

T34I; THR41ILE

Links:

UniProtKB: P35222#VAR_017630; OMIM: 116806.0011; dbSNP: rs121913413

NCBI 1000 Genomes Browser:

rs121913413

Molecular consequence:

NM_001098209.2:c.122C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001098210.2:c.122C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330729.2:c.101C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001904.4:c.122C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Desmoid disease, hereditary (DESMD)
Synonyms:: Fibromatosis, familial infiltrative
Identifiers:: MedGen: C1851124; Orphanet: 873; OMIM: 135290

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005049526	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 10, 2024)	somatic	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

SCV005049526

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 10, 2024)

somatic

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	somatic	yes	not provided	not provided	not provided	not provided	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 Clinical Genomics Laboratory, Washington University in St. Louis, SCV005049526.1

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

Description

A CTNNB1 c.122C>T (p.Thr41Ile) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in several individuals with desmoid-type fibromatosis, particularly pediatric cases (Trautmann M et al., PMID: 32099073; An J et al., PMID: 33914771) in addition to pilomatricomas (Akasaka E et al., PMID: 28651848; Chan EF et al., PMID: 10192393). It has also been reported in numerous different types of malignancies in the cancer database COSMIC (COSV62688008). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The CTNNB1 c.122C>T (p.Thr41Ile) variant resides within a Gsk3b phosphorylation site of the CTNNB1 gene that is defined as a critical region and constitutes a mutational hotspot (Trautmann M et al., PMID: 32099073). Functional studies show that the p.Thr41Ile variant is predicted to confer a gain of function to the CTNNB1 protein as demonstrated by nuclear accumulation of CTNNB1 in culture, indicating that this variant impacts protein function (Garcia-Rostan G et al., PMID: 10213482). Based on an internally developed protocol informed by the ACMG/AMP guidelines (18), and gene-specific practices from the ClinGen Criteria Specification Registry, the CTNNB1 c.122C>T (p.Thr41Ile) variant is classified as likely pathogenic.

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

Last Updated: Jun 17, 2024

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