ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5774C>A (p.Pro1925His)

gnomAD frequency: 0.00006  dbSNP: rs762682111
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235310 SCV000292906 uncertain significance not provided 2016-02-29 criteria provided, single submitter clinical testing This variant is denoted APC c.5774C>A at the cDNA level, p.Pro1925His (P1925H) at the protein level, and results in the change of a Proline to a Histidine (CCC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Pro1925His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Pro1925His occurs at a position that is not conserved and is located in the 20-amino acid repeat beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Pro1925His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000465428 SCV000552785 likely benign Familial adenomatous polyposis 1 2024-01-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000561053 SCV000672491 benign Hereditary cancer-predisposing syndrome 2021-09-08 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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 RCV000561053 SCV001342788 likely benign Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193573 SCV001362487 uncertain significance not specified 2019-12-09 criteria provided, single submitter clinical testing Variant summary: APC c.5774C>A (p.Pro1925His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249892 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (4.8e-05 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5774C>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three 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.
Baylor Genetics RCV000465428 SCV001481667 uncertain significance Familial adenomatous polyposis 1 2020-06-22 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4 RCV000561053 SCV002527988 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-09 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235310 SCV004219596 likely benign not provided 2023-01-12 criteria provided, single submitter clinical testing

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