Submissions for variant NM_000038.6(APC):c.273G>A (p.Met91Ile)

gnomAD frequency: 0.00001  dbSNP: rs745394881

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775117	SCV000909225	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 91 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 3/251468 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	RCV002534172	SCV000959705	uncertain significance	Familial adenomatous polyposis 1	2022-01-30	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs745394881, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 91 of the APC protein (p.Met91Ile). This variant has not been reported in the literature in individuals affected with APC-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 630108).
Baylor Genetics	RCV002534172	SCV004204597	uncertain significance	Familial adenomatous polyposis 1	2023-06-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775117	SCV005025836	likely benign	Hereditary cancer-predisposing syndrome	2023-11-21	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004997286	SCV005623136	uncertain significance	not provided	2024-07-12	criteria provided, single submitter	clinical testing	The APC c.273G>A (p.Met91Ile) variant has not been reported in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.