ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3084T>G (p.Ser1028Arg)

dbSNP: rs876660265
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel RCV002554571 SCV003836594 uncertain significance Familial adenomatous polyposis 1 2023-02-25 reviewed by expert panel curation The c.3084T>G variant in APC is a missense variant predicted to cause the substitution of serine by arginine at codon 1028 (p.Ser1028Arg). Another missense variant c.3084T>A (p.Ser1028Arg) at the same nucleotide position leading to the same amino acid change has been classified as Likely Pathogenic for FAP according to the APC VCEP specifications (PS1_Moderate). Another missense variant c.3083G>T (p.Ser1028Ile) in the same codon leading to a different amino acid change has been classified as Likely Pathogenic for FAP according to the APC VCEP specifications (PM5_Supporting). This variant was identified in 1 proband with polyposis not meeting phenotype criteria (PS4_variable not met; Invitae internal data). Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In Summary, due to insufficient evidence, this variant is a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS1_Moderate, PM2_Supporting, PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
Invitae RCV002554571 SCV001234439 uncertain significance Familial adenomatous polyposis 1 2019-04-08 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 1028 of the APC protein (p.Ser1028Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with APC-related conditions. This variant is not present in population databases (ExAC no frequency).
CeGaT Center for Human Genetics Tuebingen RCV001200168 SCV001371058 uncertain significance not provided 2020-04-01 criteria provided, single submitter clinical testing

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