Submissions for variant NM_000038.6(APC):c.3628C>T (p.His1210Tyr)

gnomAD frequency: 0.00004  dbSNP: rs145181563

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515908	SCV000166030	uncertain significance	Familial adenomatous polyposis 1	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1210 of the APC protein (p.His1210Tyr). This variant is present in population databases (rs145181563, gnomAD 0.002%). 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: 135698). 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.
Ambry Genetics	RCV000129238	SCV000183995	likely benign	Hereditary cancer-predisposing syndrome	2023-03-28	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.
Color Diagnostics, LLC DBA Color Health	RCV000129238	SCV000905977	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1210 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 3/250592 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.
Baylor Genetics	RCV002515908	SCV004199465	uncertain significance	Familial adenomatous polyposis 1	2023-10-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997376	SCV004837815	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1210 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 3/250592 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002515908	SCV005402173	uncertain significance	Familial adenomatous polyposis 1	2024-04-04	criteria provided, single submitter	clinical testing	The APC c.3628C>T (p.His1210Tyr) missense change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001357972	SCV005624310	uncertain significance	not provided	2023-11-04	criteria provided, single submitter	clinical testing	The APC c.3628C>T (p.His1210Tyr) variant has not been reported in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.000048 (2/41434 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357972	SCV001553587	pathogenic	not provided		no assertion criteria provided	clinical testing