Submissions for variant NM_000038.6(APC):c.4886A>G (p.His1629Arg)

dbSNP: rs1064796305

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478092	SCV000572889	uncertain significance	not provided	2017-02-10	criteria provided, single submitter	clinical testing	This variant is denoted APC c.4886A>G at the cDNA level, p.His1629Arg (H1629R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC His1629Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. APC His1629Arg occurs at a position that is conserved in mammals and is located in the 20-aa repeat B-catenin downregulating domain as well as the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC His1629Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000775773	SCV000910217	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 1629 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 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526653	SCV001396634	uncertain significance	Familial adenomatous polyposis 1	2024-06-05	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 1629 of the APC protein (p.His1629Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer (PMID: 35534218). ClinVar contains an entry for this variant (Variation ID: 423224). 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	RCV000775773	SCV002634997	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-05	criteria provided, single submitter	clinical testing	The p.H1629R variant (also known as c.4886A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 4886. The histidine at codon 1629 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with prostate cancer (So MK et al. Investig Clin Urol, 2022 May;63:294-300). This amino acid position is well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004802074	SCV005424645	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 1629 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 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.