Submissions for variant NM_000038.6(APC):c.3415A>C (p.Lys1139Gln)

gnomAD frequency: 0.00001  dbSNP: rs201550951

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586988	SCV000209514	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528)
Ambry Genetics	RCV000159549	SCV000217820	likely benign	Hereditary cancer-predisposing syndrome	2023-01-19	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.
Invitae	RCV003534406	SCV000282741	likely benign	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159549	SCV000681598	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamine at codon 1139 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 hereditary cancer in the literature. This variant has been identified in 10/250914 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	RCV001818351	SCV000694032	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: APC c.3415A>C (p.Lys1139Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250914 control chromosomes in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3415A>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=2) and VUS (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001818351	SCV002070056	uncertain significance	not specified	2020-01-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.3415A>C, in exon 16 that results in an amino acid change, p.Lys1139Gln. This sequence change does not appear to have been previously described in patients with APC-related disorders and has been described in the gnomAD database with a low population frequency of 0.089% in Ashkenazi Jewish subpopulation (dbSNP rs201550951). The p.Lys1139Gln change affects a highly conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys1139Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys1139Gln change remains unknown at this time.
Sema4, Sema4	RCV000159549	SCV002535516	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586988	SCV004222520	uncertain significance	not provided	2023-06-26	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00089 (9/10062 chromosomes in Ashkenazi Jewish 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 conflicting predictions that this variant is benign or 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	RCV000211910	SCV000591140	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Lys1139Gln variant has not been reported in the literature nor previously identified by our laboratory. This residue is conserved in mammals but not in lower organisms, and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time.