Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000214204 | SCV000273535 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-07-08 | criteria provided, single submitter | clinical testing | The p.H392R variant (also known as c.1175A>G), located in coding exon 9 of the APC gene, results from an A to G substitution at nucleotide position 1175. The histidine at codon 392 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV003650475 | SCV001396386 | uncertain significance | Familial adenomatous polyposis 1 | 2024-01-19 | 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 392 of the APC protein (p.His392Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 230106). 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. |
Department of Pathology and Laboratory Medicine, |
RCV001358135 | SCV001553795 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The APC p.His333Arg variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs876658392) and in ClinVar (classified as a VUS by Ambry Genetics for hereditary cancer-predisposing syndrome). The variant was identified in control databases in 1 of 250588 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: Latino in 1 of 34498 chromosomes (freq: 0.000029); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.His333 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |