ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2218G>C (p.Ala740Pro)

gnomAD frequency: 0.00001  dbSNP: rs587781394
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129237 SCV000183994 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-31 criteria provided, single submitter clinical testing The p.A740P variant (also known as c.2218G>C), located in coding exon 15 of the APC gene, results from a G to C substitution at nucleotide position 2218. The alanine at codon 740 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in a cohort of triple-negative breast cancer patients undergoing multigene panel testing; the same patient also had the APC p.Ser2260Asn (c.6779G>A) alteration (Lovejoy LA et al. Austin J Cancer Clin Res. 2018 Jun;5(1)). 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 RCV003460891 SCV000260671 uncertain significance Familial adenomatous polyposis 1 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 740 of the APC protein (p.Ala740Pro). This variant is present in population databases (rs587781394, 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: 140956). 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.
Color Diagnostics, LLC DBA Color Health RCV000129237 SCV000686883 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-23 criteria provided, single submitter clinical testing This missense variant replaces alanine with proline at codon 740 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 3/281424 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.
GeneDx RCV003159100 SCV003852941 uncertain significance not provided 2023-02-28 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; Observed with another APC variant (S2260N) in an individual with personal and family history of breast cancer; however, it is unknown whether the two APC variants were on the same (in cis) or opposite (in trans) allele (Lovejoy et al., 2018); This variant is associated with the following publications: (PMID: 31395942, Lovejoy2018, 18199528)
Baylor Genetics RCV003460891 SCV004197542 uncertain significance Familial adenomatous polyposis 1 2023-10-27 criteria provided, single submitter clinical testing

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