• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
CTNNA1 (HGNC:2509) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
catenin alpha 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
CAP102
%HI
2.28(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.97(Read more about gnomAD pLI score)
LOEUF
0.31(Read more about gnomAD LOEUF score)
Cytoband
5q31.2
Genomic Coordinates
GRCh37/hg19: chr5:138089114-138270723 NCBI Ensembl UCSC
GRCh38/hg38: chr5:138753425-138935034 NCBI Ensembl UCSC
MANE Select Transcript
NM_001903.5 ENST00000302763.12 (Read more about MANE Select)
Function
Associates with the cytoplasmic domain of a variety of cadherins. The association of catenins to cadherins produces a complex which is linked to the actin filament network, and which seems to be of primary importance for cadherins cell-adhesion properties. Can associate with both E- and N-cadherins. Originally believed to be a stable component of E-cadherin/catenin adhesion complexes and to mediate the linkage of cadherins to the actin cytoskeleton at adherens junctions. In contrast, cortical ac... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-36628
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
10/12/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • hereditary diffuse gastric cancer Monarch
HI Evidence:
  • PUBMED: 32051609
    Clark et al. (2020) De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers. The 33 individuals with detailed history available were from 29 different families. Among the 29 different families there were a total of 21 unique CTNNA1 LOF variants, with only CTNNA1 c.2023C>T (p.Gln675*) being previously reported in the literature. Of those with LOF variants, all affected probands had negative CDH1 testing, and no individuals had another pathogenic/likely pathogenic variant identified in any high or moderate risk cancer susceptibility gene. Four (12%) individuals had a personal history of diffuse gastric cancer, which was significantly greater than the 0.8% (1240/151,425) of the tested cohort with gastric cancer (p = 0.0002). Twenty-two (67%) individuals had a personal history of invasive breast cancer or ductal carcinoma in situ, excluding 1 individual with known lobular carcinoma in situ (LCIS), which was significantly greater than the 34% (52,093/151,425) of the tested cohort with breast cancer (p = 0.0002). Of the 7 (21%) individuals who were unaffected with cancer, the majority (5 individuals) had a family history of gastric and/or breast cancer in a first-degree relative.
  • PUBMED: 29330337
    Weren et al. (2018) sequenced a large cohort of unexplained young and/or familial patients with Gastric Cancer (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted NGS approach. There was one Polish patient who had gastric cancer at 30 yrs old carried a p.Asn443fs variant in CTNNA1. Her father also had gastric cancer at age of 47. There was a Dutch patient with Hereditary Diffuse Gastric Cancer at age of 40 carried a p.Arg330fs variant in CTNNA1. Her mother and daughter also carried the same variant but didn’t have gastric cancer phenotype.
  • PUBMED: 33326660
    Felicio et al. (2021) aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). One patient (ID 563) with breast cancer family history and diagnosis of breast cancer at age of 39 had a CTNNA1 c.1206_1207insCC, p.(Val403fs) variant.
  • PUBMED: 26182300
    Hansford et al. (2015) Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for hereditary diffuse gastric cancer (HDGC). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. In CDH1 mutation-negative index cases, two novel truncating mutations in CTNNA1 (α-catenin) (p.N71fs and p.R129X) were found in 2 unrelated HDGC families. The proband (Dx at 22 yr old) with p.N71fs variant has an affected mother (Dx at 59 yr old) with the same variant. The proband with p.R129X (Dx at 72 yr old) had a father with DGC at 52 yr old (no data for CTNNA1 status). Immunohistochemical staining of tumors from both CTNNA1 mutation-positive families showed loss of α-catenin expression, suggesting the occurrence of a second hit event at the CTNNA1 locus.
  • PUBMED: 28724667
    Sun et al. (2017) A total of 8,085 consecutive unselected Chinese breast cancer patients were enrolled. Germline mutations in 46 cancer susceptibility genes were detected using a 62-gene panel. 58 mutations were identified in gastrointestinal cancer susceptibility genes, in which 42 were in DNA mismatch repair (MMR) genes, 8 in POLE, 5 in EPCAM, 2 in KIT, and 1 in CTNNA1 (NM_001903:c.1182delC, p.F394fs).
  • PUBMED: 23208944
    Majewski et al. (2013) identified a germline truncating allele c.80_81delGA, p.Arg27Thrfs*17 of α-E-catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer.
HI Evidence Comments:
PMID: 34425242. 2021, Eur J Med Genet (Review paper). Lobo et al systematically reviewed the literature searching for CTNNA1 germline variants carriers. They found 41 families carrying CTNNA1 germline variants encompassing in total 105 probands and relatives. All probands from 13 HDGC families presented DGC and their average age of onset was 40 ± 17 years; 10/13 (77%) HDGC families carried a pathogenic (P) variant. Most probands from 28 non-HDGC families developed unspecified-BC, as well as most of their relatives. In conclusion, current available data confirms an association of CTNNA1 Pathogenic variants with early-onset diffuse gastric cancer (DGC), but not with lobular breast cancer (LBC). CTNNA1 Pathogenic variants explain <2% of HDGC families and support the use of ACMG/AMP CDH1 specific variant curation guidelines, while no specific guidelines are developed for CTNNA1 variant classification. Current knowledge supports considering only CTNNA1 P variants as clinically actionable in HDGC carrying families.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000005.9) (NC_000005.10)