ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6674C>G (p.Ser2225Cys) (rs759307079)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000468017 SCV000552582 uncertain significance Familial adenomatous polyposis 1 2018-02-02 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 2225 of the APC protein (p.Ser2225Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs759307079, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411431). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000579487 SCV000681815 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780832 SCV000918430 uncertain significance not specified 2018-03-12 criteria provided, single submitter clinical testing Variant summary: APC c.6674C>G (p.Ser2225Cys) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant was observed with an allele frequency of 8.1e-06 in 245772 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (8.1e-06 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.6674C>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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