Submissions for variant NM_000038.6(APC):c.3760A>G (p.Ile1254Val)

gnomAD frequency: 0.00001  dbSNP: rs769504783

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000732064	SCV000564572	uncertain significance	not provided	2023-10-04	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
Invitae	RCV003535743	SCV000647473	uncertain significance	Familial adenomatous polyposis 1	2023-10-12	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 1254 of the APC protein (p.Ile1254Val). This variant is present in population databases (rs769504783, gnomAD 0.005%). 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: 418012). 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	RCV000564208	SCV000667465	likely benign	Hereditary cancer-predisposing syndrome	2022-09-23	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	RCV000564208	SCV000681631	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1254 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 3/281230 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.
Eurofins Ntd Llc (ga)	RCV000732064	SCV000859952	uncertain significance	not provided	2018-03-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002525751	SCV004203334	uncertain significance	Familial adenomatous polyposis 1	2023-07-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003962331	SCV004791964	uncertain significance	APC-related condition	2024-02-27	criteria provided, single submitter	clinical testing	The APC c.3760A>G variant is predicted to result in the amino acid substitution p.Ile1254Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.