ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3374T>C (p.Val1125Ala) (rs377278397)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119206 SCV000153948 benign Familial adenomatous polyposis 1 2017-12-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130570 SCV000185441 likely benign Hereditary cancer-predisposing syndrome 2017-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
GeneDx RCV000235422 SCV000292454 likely benign not specified 2017-10-27 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.
Illumina Clinical Services Laboratory,Illumina RCV000368182 SCV000452004 likely benign APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588540 SCV000694030 likely benign not provided 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The APC c.3374T>C (p.Val1125Ala) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 69/121016 control chromosomes (including one homozygote), predominantly observed in the East Asian subpopulation at a frequency of 0.0077925 (67/8598). This frequency is about 109 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. This variant has been reported in patients with familial adenomatous polyposis (FAP) and other gastrointestinal polyposis/cancers however without strong evidence for pathogenicity (Chang_2016, Kohda_2016, Li_2015, Grant_2015, Azzopard_2008). In a Chinese family, this variant was found in five affected members with FAP syndrome suggesting that it could have co-segregated with disease in the family (Li_2015). Meanwhile, it cannot be ruled out that other undetected pathogenic variants could have actually explained the phenotype in the family. In addition, pathogenicity based on the family data is contradicted by the variants allele frequency in East Asian cohort from ExAC. Comparison of the variants allele frequency in 200 sporadic adenomatous polyposis patients (Li_2015) and in East Asian cohort from ExAC does not indicate the variant is a significant risk factor for sporadic adenomatous polyposis (OR: 1.644, CI: 0.6551 to 4.1282, p= 0.2895). In ClinVar, while two diagnostic centers have classified this variant as likely benign/benign, one has classified it as uncertain significance. Taken together, this variant is classified as likely benign.
Counsyl RCV000119206 SCV000786153 likely benign Familial adenomatous polyposis 1 2018-03-12 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677781 SCV000803937 uncertain significance Neoplasm of the liver 2017-01-12 criteria provided, single submitter clinical testing
Color RCV000130570 SCV000902644 likely benign Hereditary cancer-predisposing syndrome 2016-08-26 criteria provided, single submitter clinical testing

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