Submissions for variant NM_000038.6(APC):c.3275A>C (p.His1092Pro)

dbSNP: rs587779788

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115080	SCV000148989	uncertain significance	not provided	2022-12-22	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)
Counsyl	RCV000412266	SCV000488020	uncertain significance	Familial adenomatous polyposis 1	2015-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412266	SCV000647437	uncertain significance	Familial adenomatous polyposis 1	2024-04-30	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1092 of the APC protein (p.His1092Pro). This variant is not present in population databases (gnomAD no frequency). 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: 127286). 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.
Ambry Genetics	RCV000570435	SCV000667592	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.H1092P variant (also known as c.3275A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 3275. The histidine at codon 1092 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000412266	SCV000838102	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570435	SCV001735614	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with proline at codon 1092 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 hereditary cancer in the literature. This variant has not been identified 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.
Sema4, Sema4	RCV000570435	SCV002533248	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000412266	SCV004018820	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.