Submissions for variant NM_000038.6(APC):c.4424C>T (p.Ala1475Val)

gnomAD frequency: 0.00005  dbSNP: rs375380414

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165744	SCV000216487	likely benign	Hereditary cancer-predisposing syndrome	2023-03-30	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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210169	SCV000266142	uncertain significance	Colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV002516489	SCV000647516	uncertain significance	Familial adenomatous polyposis 1	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1475 of the APC protein (p.Ala1475Val). This variant is present in population databases (rs375380414, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of cancer and polyposis and colon cancer (PMID: 26845104, 28717660). ClinVar contains an entry for this variant (Variation ID: 186197). 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	RCV000165744	SCV000681665	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1475 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 been reported in an individual affected with polyposis and colon cancer (PMID: 26845104). This variant has been identified in 5/251072 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607446	SCV000731387	uncertain significance	not specified	2017-02-25	criteria provided, single submitter	clinical testing	The p.Ala1475Val variant in APC has been reported in one individual with colorec tal cancer (Shirts 2016) and has also been reported in ClinVar (Variation ID 186 197). This variant has also been identified in 1/66712 of European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375380414). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Ala1475Val variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985303	SCV001133337	uncertain significance	not provided	2019-02-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000985303	SCV002012986	uncertain significance	not provided	2020-01-28	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with a personal or family history including colon cancer and polyposis (Shirts 2016); This variant is associated with the following publications: (PMID: 26845104, 28717660)
Baylor Genetics	RCV002516489	SCV004199532	uncertain significance	Familial adenomatous polyposis 1	2023-10-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995448	SCV004837933	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1475 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 been reported in an individual affected with polyposis and colon cancer (PMID: 26845104). This variant has been identified in 5/251072 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.