Submissions for variant NM_000038.6(APC):c.8310C>G (p.His2770Gln)

gnomAD frequency: 0.00001  dbSNP: rs200160084

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574806	SCV000672505	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-22	criteria provided, single submitter	clinical testing	The p.H2770Q variant (also known as c.8310C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 8310. The histidine at codon 2770 is replaced by glutamine, an amino acid with highly similar properties. 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.
Invitae	RCV003652031	SCV000941000	uncertain significance	Familial adenomatous polyposis 1	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2770 of the APC protein (p.His2770Gln). 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: 485095). 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.
GeneDx	RCV001555940	SCV001777434	uncertain significance	not provided	2023-01-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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)
Baylor Genetics	RCV002528951	SCV004195594	uncertain significance	Familial adenomatous polyposis 1	2023-10-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000574806	SCV004358676	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 2770 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 1/250916 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.
PreventionGenetics, part of Exact Sciences	RCV003905490	SCV004718811	uncertain significance	APC-related condition	2023-12-13	criteria provided, single submitter	clinical testing	The APC c.8310C>G variant is predicted to result in the amino acid substitution p.His2770Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/485095/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.