Submissions for variant NM_000038.6(APC):c.8524T>G (p.Ser2842Ala)

gnomAD frequency: 0.00001  dbSNP: rs587780610

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122813	SCV000166070	uncertain significance	Familial adenomatous polyposis 1	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 2842 of the APC protein (p.Ser2842Ala). This variant is present in population databases (rs587780610, gnomAD 0.006%). 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: 135728). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APC function (PMID: 22434720). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Mendelics	RCV000122813	SCV000838163	likely benign	Familial adenomatous polyposis 1	2024-04-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001017958	SCV001179128	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	The p.S2842A variant (also known as c.8524T>G), located in coding exon 15 of the APC gene, results from a T to G substitution at nucleotide position 8524. The serine at codon 2842 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV001017958	SCV001352928	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 2842 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). An experimental study reported this variant did not affect binding of APC to PDZ domain containing partners (PMID: 22434720). This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/250534 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.
PreventionGenetics, part of Exact Sciences	RCV003415925	SCV004113763	uncertain significance	APC-related disorder	2023-05-25	criteria provided, single submitter	clinical testing	The APC c.8524T>G variant is predicted to result in the amino acid substitution p.Ser2842Ala. To our knowledge, this variant has not been reported in individuals with APC-related conditions. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112179815-T-G) and interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/135728/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000122813	SCV004204163	uncertain significance	Familial adenomatous polyposis 1	2024-01-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997392	SCV004835828	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 2842 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). An experimental study reported this variant did not affect binding of APC to PDZ domain containing partners (PMID: 22434720). This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/250534 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.