ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1264G>A (p.Glu422Lys)

gnomAD frequency: 0.00002  dbSNP: rs755069015
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003535731 SCV000552529 uncertain significance Familial adenomatous polyposis 1 2023-10-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 422 of the APC protein (p.Glu422Lys). This variant is present in population databases (rs755069015, gnomAD 0.004%). 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: 411392). 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. 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.
Color Diagnostics, LLC DBA Color Health RCV001184708 SCV001350746 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-13 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 422 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 6/250676 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.
Ambry Genetics RCV001184708 SCV002676318 likely benign Hereditary cancer-predisposing syndrome 2021-12-10 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Baylor Genetics RCV002526444 SCV004195739 uncertain significance Familial adenomatous polyposis 1 2023-10-19 criteria provided, single submitter clinical testing

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