Submissions for variant NM_000038.6(APC):c.5779C>A (p.Leu1927Ile)

gnomAD frequency: 0.00001  dbSNP: rs730881253

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588338	SCV000209533	uncertain significance	not provided	2022-09-16	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); 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])
Invitae	RCV003743596	SCV000254027	uncertain significance	Familial adenomatous polyposis 1	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1927 of the APC protein (p.Leu1927Ile). This variant is not present in population databases (gnomAD no frequency). 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: 181810). 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	RCV000218036	SCV000275411	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-25	criteria provided, single submitter	clinical testing	The p.L1927I variant (also known as c.5779C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 5779. The leucine at codon 1927 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000199957	SCV000489160	uncertain significance	Familial adenomatous polyposis 1	2016-08-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588338	SCV000694084	uncertain significance	not provided	2016-05-27	criteria provided, single submitter	clinical testing	Variant summary: The APC c.5779C>A (p.Leu1927Ile) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120712 control chromosomes. Multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications 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 was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000218036	SCV000911961	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 1927 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 APC-related disorders in the literature. This variant has not been identified 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.
Baylor Genetics	RCV000199957	SCV001481334	uncertain significance	Familial adenomatous polyposis 1	2019-08-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000199957	SCV003843163	uncertain significance	Familial adenomatous polyposis 1	2022-11-22	criteria provided, single submitter	clinical testing	The APC c.5779C>A (p.Leu1927Ile) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with APC-related familial adenomatous polyposis. 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.
Myriad Genetics, Inc.	RCV003315948	SCV004018740	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.