Submissions for variant NM_000038.6(APC):c.6694C>G (p.His2232Asp)

gnomAD frequency: 0.00004  dbSNP: rs730881256

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656749	SCV000209540	uncertain significance	not provided	2023-10-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21859464, 18199528, 35260767)
Invitae	RCV003650407	SCV000259792	uncertain significance	Familial adenomatous polyposis 1	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 2232 of the APC protein (p.His2232Asp). This variant is present in population databases (rs730881256, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 181815). 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 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.
Ambry Genetics	RCV000216441	SCV000273988	likely benign	Hereditary cancer-predisposing syndrome	2023-06-22	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.
Counsyl	RCV000204441	SCV000489562	uncertain significance	Familial adenomatous polyposis 1	2016-10-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656749	SCV000600136	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with colorectal adenomas (PMID: 18199528 (2008)). The frequency of this variant in the general population, 0.000023 (3/128660 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000216441	SCV000681818	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 2232 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 been reported in an individual affected with 11 to 99 colorectal adenomas (PMID: 18199528). This variant has also been reported in a young individual affected with synchronous bifocal colorectal adenocarcinoma, however, this individual also carried pathogenic variants in PMS2 and POLE (PMID: 35260767). This variant has been identified in 4/281720 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.
Sema4, Sema4	RCV000216441	SCV002534441	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000204441	SCV004018554	uncertain significance	Familial adenomatous polyposis 1	2023-02-17	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656749	SCV001548600	uncertain significance	not provided		no assertion criteria provided	clinical testing