Submissions for variant NM_000038.6(APC):c.7174C>A (p.Pro2392Thr)

gnomAD frequency: 0.00003  dbSNP: rs730881257

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159568	SCV000209543	uncertain significance	not provided	2024-01-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18199528, 31980526, 35534704)
Ambry Genetics	RCV000219951	SCV000273674	likely benign	Hereditary cancer-predisposing syndrome	2020-08-21	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.
Counsyl	RCV000409928	SCV000489561	uncertain significance	Familial adenomatous polyposis 1	2016-10-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409928	SCV000552493	benign	Familial adenomatous polyposis 1	2024-08-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219951	SCV000681852	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 2392 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 2/250282 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	RCV000159568	SCV001133361	uncertain significance	not provided	2019-07-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192797	SCV001361156	uncertain significance	not specified	2019-04-04	criteria provided, single submitter	clinical testing	Variant summary: APC c.7174C>A (p.Pro2392Thr) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245024 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.7174C>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000159568	SCV002011085	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000219951	SCV002527479	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-21	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409928	SCV004018738	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	RCV000409928	SCV004206673	uncertain significance	Familial adenomatous polyposis 1	2023-04-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998420	SCV004843513	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 2392 of the APC protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (DOI: 10.1101/2021.04.15.21255554v2). This variant has been identified in 2/250282 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.
Fulgent Genetics, Fulgent Genetics	RCV005042307	SCV005667887	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-01-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192797	SCV005873275	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Classification criteria: BP1, BS1