Submissions for variant NM_000038.6(APC):c.2677G>A (p.Glu893Lys)

gnomAD frequency: 0.00001  dbSNP: rs199740875

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164189	SCV000214810	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	clinical testing	The p.E893K variant (also known as c.2677G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 2677. The glutamic acid at codon 893 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000409913	SCV000489375	uncertain significance	Familial adenomatous polyposis 1	2016-10-03	criteria provided, single submitter	clinical testing
Invitae	RCV000409913	SCV000552459	uncertain significance	Familial adenomatous polyposis 1	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 893 of the APC protein (p.Glu893Lys). This variant is present in population databases (rs199740875, gnomAD 0.006%). 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: 41501). 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.
Color Diagnostics, LLC DBA Color Health	RCV000164189	SCV000681546	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 893 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 6/250796 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	RCV001174835	SCV001338208	uncertain significance	not specified	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: APC c.2677G>A (p.Glu893Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 394116 control chromosomes, predominantly at a frequency of 4.5e-05 (8/177,752 alleles) within the Non-Finnish European subpopulation in the gnomAD database (gnomAD v2.1 exomes dataset and gnomAD v3 genomes dataset). This frequency is somewhat lower than the estimated maximal expected allele frequency of a pathogenic APC variant (7.1e-05). The variant was reported in the literature as an incidental finding in 1/572 individuals in an exome sequencing study (i.e. the ClinSeq study, involving participants of 45-65 years of age, selected for a range of atherosclerosis phenotypes, but not for personal or family histories of cancer) (Johnston_2012). To our knowledge, no occurrence of c.2677G>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign, until additional information becomes available.
GeneDx	RCV000034383	SCV001822652	uncertain significance	not provided	2019-12-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29106415, 29876005, 25801821, 22703879)
Myriad Genetics, Inc.	RCV003315544	SCV004018826	likely benign	Familial adenomatous polyposis 1	2023-02-23	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034383	SCV000043117	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.