Submissions for variant NM_000038.6(APC):c.3780G>C (p.Gln1260His)

dbSNP: rs763668164

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003465409	SCV000768166	uncertain significance	Familial adenomatous polyposis 1	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1260 of the APC protein (p.Gln1260His). This variant is present in population databases (rs763668164, gnomAD 0.0009%). 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: 537494). 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	RCV001575978	SCV001803079	uncertain significance	not provided	2022-09-03	criteria provided, single submitter	clinical testing	Not observed at 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
Ambry Genetics	RCV002343321	SCV002622552	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-12	criteria provided, single submitter	clinical testing	The p.Q1260H variant (also known as c.3780G>C), located in coding exon 15 of the APC gene, results from a G to C substitution at nucleotide position 3780. The glutamine at codon 1260 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly 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.
Baylor Genetics	RCV003465409	SCV004200331	uncertain significance	Familial adenomatous polyposis 1	2023-09-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004073	SCV004833706	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 1260 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 1/250328 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.