Submissions for variant NM_000038.6(APC):c.1391A>G (p.His464Arg)

dbSNP: rs730881236

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159533	SCV000209493	uncertain significance	not provided	2020-09-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with Lynch-related cancer or polyps (Yurgelun 2015); This variant is associated with the following publications: (PMID: 25980754)
Ambry Genetics	RCV000217103	SCV000274080	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-21	criteria provided, single submitter	clinical testing	The p.H464R variant (also known as c.1391A>G), located in coding exon 10 of the APC gene, results from an A to G substitution at nucleotide position 1391. The histidine at codon 464 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps. (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). 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.
Color Diagnostics, LLC DBA Color Health	RCV000217103	SCV000905881	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 464 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 1/250352 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.
Invitae	RCV003534400	SCV000935205	uncertain significance	Familial adenomatous polyposis 1	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 464 of the APC protein (p.His464Arg). This variant is present in population databases (rs730881236, gnomAD 0.006%). This missense change has been observed in individual(s) with a Lynch syndrome cancer and/or polyposis (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 181788). 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.
Baylor Genetics	RCV000795734	SCV001482684	uncertain significance	Familial adenomatous polyposis 1	2020-08-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].