Submissions for variant NM_000038.6(APC):c.4597A>G (p.Asn1533Asp)

gnomAD frequency: 0.00001  dbSNP: rs730881226

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159513	SCV000209468	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with advanced cancer (Mandelker 2017); This variant is associated with the following publications: (PMID: 20136519, 28873162, 30972172)
Color Diagnostics, LLC DBA Color Health	RCV000583326	SCV000686979	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-13	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 1533 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 hereditary cancer in the literature. This variant has been identified in 3/250346 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003474816	SCV000953528	uncertain significance	Familial adenomatous polyposis 1	2022-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1533 of the APC protein (p.Asn1533Asp). This variant is present in population databases (rs730881226, gnomAD 0.003%). 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: 181772). 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	RCV000583326	SCV001184528	likely benign	Hereditary cancer-predisposing syndrome	2024-07-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Baylor Genetics	RCV003474816	SCV004201491	uncertain significance	Familial adenomatous polyposis 1	2024-03-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998395	SCV004837952	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 1533 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 hereditary cancer in the literature. This variant has been identified in 3/250346 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.