Submissions for variant NM_000038.6(APC):c.3220A>G (p.Thr1074Ala)

gnomAD frequency: 0.00001  dbSNP: rs962456431

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491326	SCV000579796	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-08	criteria provided, single submitter	clinical testing	The p.T1074A variant (also known as c.3220A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 3220. The threonine at codon 1074 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004568608	SCV000817004	uncertain significance	Familial adenomatous polyposis 1	2024-06-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1074 of the APC protein (p.Thr1074Ala). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 428104). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000491326	SCV000909030	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1074 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250420 chromosomes 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003114615	SCV002010888	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114615	SCV003799605	uncertain significance	not provided	2022-04-29	criteria provided, single submitter	clinical testing	The APC c.3220A>G; p.Thr1074Ala variant (rs962456431), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 428104). This variant is only observed on 3 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1074 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.18). The vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). However, due to limited information, the clinical significance of this missense variant is uncertain at this time. References: Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43.
GeneDx	RCV003114615	SCV004030611	uncertain significance	not provided	2023-08-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a patient with hereditary polyposis (Dz et al., 2021); This variant is associated with the following publications: (PMID: 18199528, Dz2021[Case Report])