Submissions for variant NM_000038.6(APC):c.689G>A (p.Arg230His)

gnomAD frequency: 0.00003  dbSNP: rs587780545

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119182	SCV000153918	uncertain significance	Familial adenomatous polyposis 1	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the APC protein (p.Arg230His). This variant is present in population databases (rs587780545, gnomAD 0.01%). This missense change has been observed in individual(s) with colon cancer and/or pancreatic cancer (PMID: 28125075, 32980694, 35189564). ClinVar contains an entry for this variant (Variation ID: 132732). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Color Diagnostics, LLC DBA Color Health	RCV000579594	SCV000681832	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 230 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 individuals affected with colorectal, uterine, or pancreatic cancer (PMID: 28125075, 29684080, 32980694, 35189564), as well as in 37 unaffected individuals in a pancreatic case control study (PMID: 32980694). This variant has been identified in 12/282562 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589003	SCV000694102	uncertain significance	not provided	2016-09-02	criteria provided, single submitter	clinical testing	Variant summary: The APC c.689G>A (p.Arg230His) variant involves the alteration of a conserved nucleotide. Arg230 is conserved through species and located in the Adenomatous polyposis coli protein domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/120512 control chromosomes at a frequency of 0.0000664, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Mendelics	RCV000119182	SCV001136876	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579594	SCV001188026	likely benign	Hereditary cancer-predisposing syndrome	2021-12-02	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.
GeneDx	RCV000589003	SCV001824286	uncertain significance	not provided	2020-03-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Ghazani 2017); This variant is associated with the following publications: (PMID: 28125075)
Sema4, Sema4	RCV000579594	SCV002526808	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-24	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589003	SCV004220482	uncertain significance	not provided	2023-04-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000047 (6/129016 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colon cancer (PMID: 28125075 (2017)) and uterine carcinosarcoma (PMID: 29684080 (2018)). It was also reported in an individual with either diagnosed or suspected Familial adenomatous polyposis (FAP) (PMID: 35189564 (2022)). Analysis of this variant using a bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded a prediction that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005365007	SCV005918675	uncertain significance	Classic or attenuated familial adenomatous polyposis	2020-09-01	criteria provided, single submitter	clinical testing