Submissions for variant NM_000038.6(APC):c.3295G>A (p.Val1099Ile)

gnomAD frequency: 0.00001  dbSNP: rs730881245

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211909	SCV000209512	uncertain significance	not provided	2023-03-21	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; This variant is associated with the following publications: (PMID: 29642553, 18199528)
Ambry Genetics	RCV000159548	SCV000216891	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-01	criteria provided, single submitter	clinical testing	The p.V1099I variant (also known as c.3295G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 3295. The valine at codon 1099 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691255	SCV000819007	uncertain significance	Familial adenomatous polyposis 1	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1099 of the APC protein (p.Val1099Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with polyposis (internal data). ClinVar contains an entry for this variant (Variation ID: 181800). 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%. 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	RCV000691255	SCV000838103	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159548	SCV000905976	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1099 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 reported in individual(s) affected with polyposis (ClinVar SCV000819007.6). This variant has been identified in 1/31408 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	RCV000691255	SCV004199676	uncertain significance	Familial adenomatous polyposis 1	2023-10-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998411	SCV004839792	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1099 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31408 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.