Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV003315710 | SCV000153948 | benign | Familial adenomatous polyposis 1 | 2024-02-01 | 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 | 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. |
Gene |
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 Laboratory Services, |
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, |
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 Diagnostics, |
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, |
RCV000235422 | SCV001158644 | likely benign | not specified | 2018-10-23 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000130570 | SCV002533304 | likely benign | Hereditary cancer-predisposing syndrome | 2020-08-14 | criteria provided, single submitter | curation | |
Myriad Genetics, |
RCV003315710 | SCV004018793 | 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, |
RCV000235422 | SCV004025052 | benign | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
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. |