Submissions for variant NM_000038.6(APC):c.2658G>T (p.Gln886His)

dbSNP: rs587780593

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122768	SCV000166025	uncertain significance	Familial adenomatous polyposis 1	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 886 of the APC protein (p.Gln886His). This variant is present in population databases (rs587780593, gnomAD 0.0009%). 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: 135694). 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.
Counsyl	RCV000122768	SCV000488361	uncertain significance	Familial adenomatous polyposis 1	2016-03-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000485846	SCV000566342	uncertain significance	not specified	2017-05-22	criteria provided, single submitter	clinical testing	This variant is denoted APC c.2658G>T at the cDNA level, p.Gln886His (Q886H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Gln886His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Gln886His occurs at a position that is conserved through mammals and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Gln886His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574171	SCV000667464	likely benign	Hereditary cancer-predisposing syndrome	2023-03-24	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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000664308	SCV000788240	likely benign	Familial multiple polyposis syndrome	2018-04-01	criteria provided, single submitter	research	The APC variant designated as NM_000038.5:c.2658G>T (p.Gln886His) is classified as likely benign. This variant was observed in an individual in one family who was documented not to have colon polyps on colonoscopy at over 70 years old. This observation is not consistent with either attenuated or classic familial adenomatous polyposis syndromes (Grover et al. 2012, PMID:22851115). Additional family members at risk of inheriting the variant have been documented to have no colon polyps. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color Diagnostics, LLC DBA Color Health	RCV000574171	SCV000905973	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 886 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/250718 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.
Illumina Laboratory Services, Illumina	RCV001157044	SCV001318590	uncertain significance	APC-Associated Polyposis Disorders	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Myriad Genetics, Inc.	RCV003315799	SCV004018776	uncertain significance	Familial adenomatous polyposis 1	2023-02-21	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325185	SCV004031110	uncertain significance	Gastric adenocarcinoma and proximal polyposis of the stomach	2023-08-01	criteria provided, single submitter	clinical testing	The APC c.2658G>T (p.Gln886His) missense change has a maximum subpopulation frequency of 0.0008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has not been reported in the literature in individuals with APC-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.?
Baylor Genetics	RCV000122768	SCV004192071	uncertain significance	Familial adenomatous polyposis 1	2023-09-04	criteria provided, single submitter	clinical testing