Submissions for variant NM_000038.6(APC):c.6310A>G (p.Ile2104Val)

dbSNP: rs878853462

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230641	SCV000282793	uncertain significance	Familial adenomatous polyposis 1	2023-04-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2104 of the APC protein (p.Ile2104Val). 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: 236629). 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.
Counsyl	RCV000230641	SCV000489023	uncertain significance	Familial adenomatous polyposis 1	2016-08-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000583502	SCV000687071	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2104 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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.
GeneDx	RCV001775696	SCV002014017	uncertain significance	not provided	2020-08-26	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); 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
Ambry Genetics	RCV000583502	SCV004005147	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The p.I2104V variant (also known as c.6310A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 6310. The isoleucine at codon 2104 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. 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.
Myriad Genetics, Inc.	RCV000230641	SCV004019678	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000230641	SCV005052466	uncertain significance	Familial adenomatous polyposis 1	2023-11-29	criteria provided, single submitter	clinical testing