ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1554G>A (p.Thr518=) (rs546568052)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083971 SCV000166016 benign Familial adenomatous polyposis 1 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162691 SCV000213145 likely benign Hereditary cancer-predisposing syndrome 2014-07-30 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.
GeneDx RCV000435025 SCV000512063 likely benign not specified 2017-09-01 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.
Color Health, Inc RCV000162691 SCV000681473 benign Hereditary cancer-predisposing syndrome 2016-05-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586072 SCV000694000 benign not provided 2016-05-03 criteria provided, single submitter clinical testing Variant summary: The APC variant, c.1554G>A (p.Thr518Thr) causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico tools via Alamut predict no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 122/120352 (1/986 including 2 homozygotes), predominantly in the South Asian cohort, 119/16346 (1/137 including 2 homozygotes), which exceeds the estimated maximum expected allele frequency for a pathogenic APC variant of 1/16611. Therefore, suggesting that the variant of interest is a common polymorphism found in population(s) of South Asian origin. It was reported once in a patient with another causative mutation that is not specified (Scott_Hered Cancer Clin Prac_2004). Multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000435025 SCV001469899 benign not specified 2019-12-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353571 SCV000591078 benign Carcinoma of colon no assertion criteria provided clinical testing The APC p.Thr518Thr variant was identified in 1 of 224 proband chromosomes (frequency: 0.004) from individuals or families with FAP (Scott 2004). The variant was also identified in dbSNP (ID: rs546568052) “With likely benign allele”, the Clinvitae database, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as a benign variant by Invitae and as likely benign by Ambry Genetics). The variant was identified in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 119 of 16346 chromosomes (frequency: 0.00728) from a South Asian population (and in two individuals in homozygous form) as well as at lower frequencies in African, Latino and European (Non-Finnish) individuals and by the 1000 Genomes Project with a minor allele frequency of 0.0028 in an African Caribbean population, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Thr518Thr variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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, this variant meets our laboratories criteria to be classified as benign.

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