Submissions for variant NM_000038.6(APC):c.1318G>A (p.Ala440Thr)

dbSNP: rs1064793023

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590604	SCV000564563	uncertain significance	not provided	2022-12-09	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590604	SCV000693991	uncertain significance	not provided	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The APC c.1318G>A (p.Ala440Thr) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120198 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV003470521	SCV000947825	uncertain significance	Familial adenomatous polyposis 1	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 440 of the APC protein (p.Ala440Thr). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 418008). 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. 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.
Ambry Genetics	RCV001010961	SCV001171229	likely benign	Hereditary cancer-predisposing syndrome	2021-06-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001010961	SCV001353479	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 440 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 been identified in 3/250476 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.
Baylor Genetics	RCV003470521	SCV004191350	uncertain significance	Familial adenomatous polyposis 1	2023-09-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003942584	SCV004758159	uncertain significance	APC-related condition	2024-02-21	criteria provided, single submitter	clinical testing	The APC c.1318G>A variant is predicted to result in the amino acid substitution p.Ala440Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as a variant of uncertain significance by majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/418008/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.