ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3378C>G (p.Ser1126Arg)

gnomAD frequency: 0.00001  dbSNP: rs149353082
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120024 SCV000148991 likely benign not specified 2017-12-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000411300 SCV000487902 uncertain significance Familial adenomatous polyposis 1 2015-12-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000411300 SCV000552651 likely benign Familial adenomatous polyposis 1 2024-01-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985246 SCV000600080 likely benign not provided 2022-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565031 SCV000667245 likely benign Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing This alteration is classified as likely 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 RCV000565031 SCV000681594 likely benign Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001154639 SCV001316017 likely benign APC-Associated Polyposis Disorders 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Sema4, Sema4 RCV000565031 SCV002535494 likely benign Hereditary cancer-predisposing syndrome 2020-11-05 criteria provided, single submitter curation
Myriad Genetics, Inc. RCV000411300 SCV004018805 likely benign Familial adenomatous polyposis 1 2023-02-22 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120024 SCV004025053 likely benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000985246 SCV004234479 uncertain significance not provided 2023-06-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120024 SCV004804171 likely benign not specified 2024-01-05 criteria provided, single submitter clinical testing Variant summary: APC c.3378C>G (p.Ser1126Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 1613926 control chromosomes, predominantly at a frequency of 0.00051 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3378C>G has been reported in the literature in individuals affected with Colorectal cancer as well as unaffected control study participants and the authors of this report classified the variant as likely benign (example: Fujita_2022). The following publication has been ascertained in the context of this evaluation (PMID: 33309985). ClinVar contains an entry for this variant (Variation ID: 127288). Based on the evidence outlined above, the variant was classified as likely benign.
ITMI RCV000120024 SCV000084155 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000677784 SCV000591138 likely benign Carcinoma of colon no assertion criteria provided clinical testing The APC, c.3378C>G, p.Ser1126Arg variant has been observed in the literature in 1 of 148 control chromosomes in individuals increasing the likelihood this variant does not have clinical significance. It was not, however, detected in any of the 160 proband chromosomes of individuals with sporadic colorectal carcinoma (Chen_2006_16569251). It was listed in dbSNP (ID: rs149353082) and reported from 1000 genomes with a frequency of 0.001, although only 1 chromosomes was found with this variant. It was not found in the UMD or LOVD databases. It was mentioned in Clinvar (1x by GeneDx with uncertain significance). This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. Furthermore, this variant does not occur in any known important protein domain. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, and since there were fewer than 5 chromosomes identified with this variant in this analysis, the clinical significance of this variant cannot be determined with certainty although we would lean towards a more benign role, this variant is predicted benign.
3DMed Clinical Laboratory Inc RCV000677784 SCV000803940 uncertain significance Carcinoma of colon 2018-01-29 no assertion criteria provided clinical testing

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