Submissions for variant NM_000038.6(APC):c.4372C>T (p.Pro1458Ser)

gnomAD frequency: 0.00005  dbSNP: rs143796828

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034415	SCV000209525	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a healthy control individual and in an individual with atherosclerosis in published literature (Azzopardi et al., 2008; Johnston et al., 2012); This variant is associated with the following publications: (PMID: 18199528, 22703879, 26320869)
Ambry Genetics	RCV000159555	SCV000214752	likely benign	Hereditary cancer-predisposing syndrome	2021-01-15	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	RCV000196865	SCV000254014	likely benign	Familial adenomatous polyposis 1	2025-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000196865	SCV000488485	uncertain significance	Familial adenomatous polyposis 1	2016-04-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515179	SCV000611338	uncertain significance	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159555	SCV000686973	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 1458 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 individuals affected with pancreatic cancer in the literature (PMID: 28726808), but has also been observed in healthy individuals (PMID: 18199528, 22703879). This variant has been identified in 18/282574 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.
Mendelics	RCV003492325	SCV000838118	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000196865	SCV004018790	uncertain significance	Familial adenomatous polyposis 1	2023-02-22	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.
All of Us Research Program, National Institutes of Health	RCV003996164	SCV004837924	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 1458 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 individuals affected with pancreatic cancer in the literature (PMID: 28726808), but has also been observed in healthy individuals (PMID: 18199528, 22703879). This variant has been identified in 18/282574 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034415	SCV005624466	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	The APC c.4372C>T (p.Pro1458Ser) variant has been reported in the published literature along with other variants in individuals affected with bladder cancer (PMID: 26320869 (2015)), pancreatic cancer (PMID: 28726808 (2018)), and enchondromas (PMID: 31240473 (2019)). It was also detected in reportedly healthy individuals (PMID: 18199528 (2008)). The frequency of this variant in the general population, 0.00017 (6/35422 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034415	SCV000043127	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.