Submissions for variant NM_000038.6(APC):c.2110G>A (p.Val704Ile)

gnomAD frequency: 0.00006  dbSNP: rs367804502

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164801	SCV000215481	likely benign	Hereditary cancer-predisposing syndrome	2023-03-15	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	RCV003316030	SCV000253995	uncertain significance	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 704 of the APC protein (p.Val704Ile). This variant is present in population databases (rs367804502, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 185391). 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.
GeneDx	RCV000657054	SCV000293114	uncertain significance	not provided	2022-08-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency 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)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657054	SCV000600056	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00012 (3/24930 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, this variant has been reported in an individual with breast cancer (PMID: 35264596 (2022)). 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.
Counsyl	RCV000198244	SCV000785203	uncertain significance	Familial adenomatous polyposis 1	2017-06-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000198244	SCV000838087	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236550	SCV000916473	likely benign	not specified	2022-07-07	criteria provided, single submitter	clinical testing	Variant summary: APC c.2110G>A (p.Val704Ile) 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 3e-05 in 395526 control chromosomes, predominantly at a frequency of 0.00019 within the African or African-American subpopulation in the gnomAD database (v2.1 and v3.1-non-v2 datasets). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7-fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2110G>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001155352	SCV001316776	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.
Color Diagnostics, LLC DBA Color Health	RCV000164801	SCV001350172	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 704 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 been identified in 4/282154 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.
Myriad Genetics, Inc.	RCV003316030	SCV004017825	uncertain significance	Familial adenomatous polyposis 1	2023-02-16	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	RCV000198244	SCV004202004	uncertain significance	Familial adenomatous polyposis 1	2023-08-20	criteria provided, single submitter	clinical testing