Submissions for variant NM_000038.6(APC):c.2813C>G (p.Thr938Ser)

gnomAD frequency: 0.00002  dbSNP: rs1554084496

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000563275	SCV000672517	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	The p.T938S variant (also known as c.2813C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 2813. The threonine at codon 938 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985292	SCV001133316	uncertain significance	not provided	2018-11-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526896	SCV001198886	uncertain significance	Familial adenomatous polyposis 1	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 938 of the APC protein (p.Thr938Ser). This variant is not present in population databases (gnomAD no frequency). 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: 485099). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
GeneDx	RCV000985292	SCV003806042	uncertain significance	not provided	2022-08-16	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; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV002526896	SCV004200143	uncertain significance	Familial adenomatous polyposis 1	2023-09-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000563275	SCV004361149	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 938 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-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.
All of Us Research Program, National Institutes of Health	RCV004001095	SCV004839726	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 938 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-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.