ClinVar Miner

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

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119206 SCV000153948 benign Familial adenomatous polyposis 1 2020-11-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130570 SCV000185441 likely benign Hereditary cancer-predisposing syndrome 2018-11-06 criteria provided, single submitter clinical testing 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 2019-05-03 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235422 SCV000694030 benign not specified 2021-02-08 criteria provided, single submitter clinical testing Variant summary: APC c.3374T>C (p.Val1125Ala) 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 0.00061 in 251058 control chromosomes, predominantly at a frequency of 0.0081 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 113 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.3374T>C, has been reported in the literature in individuals affected with Familial Adenomatous Polyposis and other gastrointestinal polyposes/cancers, however without strong evidence for pathogenicity (example, Chang_2016, Kohda_2016, Li_2015, Grant_2015, Azzopard_2008, Tung_2016). In a Chinese family, this variant seemed to segregate with the disease in five affected members with FAP syndrome, however it cannot be ruled out that other undetected pathogenic variants could have actually explained the phenotype (Li_2015). Therefore these reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=9; VUS, n=1). Based on the evidence outlined above reflecting the consensus among peers the variant was classified as 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 Health, Inc RCV000130570 SCV000902644 likely benign Hereditary cancer-predisposing syndrome 2016-08-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588540 SCV001133322 likely benign not provided 2019-08-20 criteria provided, single submitter clinical testing
Mendelics RCV000119206 SCV001136901 benign Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000235422 SCV001158644 likely benign not specified 2018-10-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354303 SCV001548886 likely benign Carcinoma of colon no assertion criteria provided clinical testing The APC p.Val1125Ala variant was identified in 5 of 2666 proband chromosomes (frequency: 0.002) from individuals or families with colon and breast cancer (Chen 2006, Azzopardi 2008, Tung 2016). The variant was also identified in dbSNP (ID: rs377278397) as “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, likely benign by Ambry Genetics and Illumina, and benign by Invitae), Clinvitae (4x), and Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, MutDB, LOVD 3.0, and UMD-LSDB databases. The variant was identified in control databases in 167 of 276336 chromosomes at a frequency of 0.0006 in the following populations: African in 1 of 23940 chromosomes (freq. 0.00004), East Asian in 160 (1 homozygous) of 18838 chromosomes (freq. 0.008), Other in 4 of 6452 chromosomes (freq. 0.0006), South Asian in 1 of 30754 chromosomes (freq. 0.00003), and Latino in 1 of 34390 chromosomes (freq. 0.00003), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val1125Ala residue is conserved in in mammals but not in more distantly related organisms, with the variant amino acid Alanine (Ala) present in the African clawed frog, however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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