ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6691A>T (p.Ile2231Phe)

gnomAD frequency: 0.00001  dbSNP: rs534228737
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115113 SCV000149022 uncertain significance not provided 2022-09-21 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; Identified in individuals with early-onset colorectal cancer (Do et al., 2022); This variant is associated with the following publications: (PMID: 35098669, 18199528)
Ambry Genetics RCV000573892 SCV000667604 likely benign Hereditary cancer-predisposing syndrome 2022-06-15 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.
Color Diagnostics, LLC DBA Color Health RCV000573892 SCV000681817 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-26 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with phenylalanine at codon 2231 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 been reported in individuals affected with breast cancer (PMID: 29684080) and colorectal cancer (PMID: 35098669). This variant has been identified in 3/250308 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.
Invitae RCV003534343 SCV001235297 uncertain significance Familial adenomatous polyposis 1 2023-10-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2231 of the APC protein (p.Ile2231Phe). This variant is present in population databases (rs534228737, gnomAD 0.01%). 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: 127314). 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.

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