ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7105C>T (p.Pro2369Ser)

gnomAD frequency: 0.00002  dbSNP: rs377308875
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220467 SCV000277218 likely benign Hereditary cancer-predisposing syndrome 2021-08-30 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.
Invitae RCV003650501 SCV000282813 uncertain significance Familial adenomatous polyposis 1 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2369 of the APC protein (p.Pro2369Ser). This variant is present in population databases (rs377308875, gnomAD 0.005%). 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: 232940). 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.
GeneDx RCV000236554 SCV000292464 uncertain significance not provided 2022-09-01 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528)
Color Diagnostics, LLC DBA Color Health RCV000220467 SCV000681848 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 2369 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 7/249736 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280597 SCV001467807 uncertain significance not specified 2020-12-03 criteria provided, single submitter clinical testing Variant summary: APC c.7105C>T (p.Pro2369Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249736 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7105C>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4 RCV000220467 SCV002527412 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-23 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002291603 SCV002584580 uncertain significance Familial adenomatous polyposis 1 2022-08-25 criteria provided, single submitter clinical testing The APC c.7105C>T (p.Pro2369Ser) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with APC-related familial adenomatous polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002478806 SCV002775824 uncertain significance Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach 2021-10-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV002291603 SCV004200065 uncertain significance Familial adenomatous polyposis 1 2023-09-30 criteria provided, single submitter clinical testing

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