Submissions for variant NM_000038.6(APC):c.7858T>A (p.Phe2620Ile)

dbSNP: rs587781816

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130090	SCV000184919	likely benign	Hereditary cancer-predisposing syndrome	2019-03-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195856	SCV000254042	uncertain significance	Familial adenomatous polyposis 1	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2620 of the APC protein (p.Phe2620Ile). 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: 141524). 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.
Counsyl	RCV000195856	SCV000488240	uncertain significance	Familial adenomatous polyposis 1	2016-02-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000485276	SCV000565712	uncertain significance	not provided	2020-10-09	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal and family history of breast or ovarian cancer (Maxwell 2016); This variant is associated with the following publications: (PMID: 31612017, 27153395)
Color Diagnostics, LLC DBA Color Health	RCV000130090	SCV000687145	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 2620 of the APC protein in the EB1-binding domain. 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 been reported in individuals affected with hereditary breast/ovarian cancer (PMID: 27153395) but has not been identified in individuals affected with familial adenomatous polyposis. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000485276	SCV002011082	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797633	SCV002041876	uncertain significance	not specified	2021-11-30	criteria provided, single submitter	clinical testing	Variant summary: APC c.7858T>A (p.Phe2620Ile) results in a non-conservative amino acid change in the encoded protein sequence. This variant is also known as c.7804T>A (p.Phe2440Ile) in HGVS. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249960 control chromosomes (gnomAD). 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.7858T>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=6) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000195856	SCV004018739	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.
Baylor Genetics	RCV000195856	SCV004201591	uncertain significance	Familial adenomatous polyposis 1	2023-07-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997549	SCV004835731	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 2620 of the APC protein in the EB1-binding domain. 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 been reported in individuals affected with hereditary breast/ovarian cancer (PMID: 27153395) but has not been identified in individuals affected with familial adenomatous polyposis. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485276	SCV005623684	uncertain significance	not provided	2024-09-20	criteria provided, single submitter	clinical testing	The APC c.7858T>A (p.Phe2620Ile) variant has not been reported in individuals with APC-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.