Submissions for variant NM_000038.6(APC):c.1279C>A (p.His427Asn)

dbSNP: rs587779781

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766425	SCV000148977	uncertain significance	not provided	2018-12-10	criteria provided, single submitter	clinical testing	This variant is denoted APC c.1279C>A at the cDNA level, p.His427Asn (H427N) at the protein level, and results in the change of a Histidine to an Asparagine (CAT>AAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC His427Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC His427Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115068	SCV000600040	uncertain significance	not specified	2017-01-26	criteria provided, single submitter	clinical testing
Invitae	RCV003650368	SCV000647167	uncertain significance	Familial adenomatous polyposis 1	2023-06-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 127276). 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. 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. This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant is present in population databases (rs587779781, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 427 of the APC protein (p.His427Asn).
GeneKor MSA	RCV000708636	SCV000821807	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000708636	SCV001358307	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with asparagine at codon 427 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 3/250682 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.
Sema4, Sema4	RCV000708636	SCV002533902	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000115068	SCV002550579	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708636	SCV002686782	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-12	criteria provided, single submitter	clinical testing	The p.H427N variant (also known as c.1279C>A), located in coding exon 9 of the APC gene, results from a C to A substitution at nucleotide position 1279. The histidine at codon 427 is replaced by asparagine, an amino acid with similar properties. This variant was reported as a variant of unknown significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.