ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3632T>G (p.Met1211Arg) (rs575268622)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122774 SCV000166031 likely benign Familial adenomatous polyposis 1 2020-11-24 criteria provided, single submitter clinical testing
GeneDx RCV001704031 SCV000569041 likely benign not provided 2021-09-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30093976, 29641532, 25186627, 24728327)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120048 SCV000600088 uncertain significance not specified 2017-04-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568279 SCV000672492 likely benign Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Counsyl RCV000122774 SCV000784915 uncertain significance Familial adenomatous polyposis 1 2017-02-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000568279 SCV000902702 likely benign Hereditary cancer-predisposing syndrome 2016-06-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120048 SCV000916513 likely benign not specified 2018-12-07 criteria provided, single submitter clinical testing Variant summary: The variant, APC c.3632T>G (p.Met1211Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 276326 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 30.8 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 South Asian origin. The variant, c.3632T>G has been reported in the literature in individuals affected with breast and colorectal cancer (Chakrabarty_2017, Tung_2015, Chakrabarty _2017). This report does 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign (2X) and uncertain significance (3X)). Based on the evidence outlined above, the variant was classified as likely benign.
ITMI RCV000120048 SCV000084183 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000122774 SCV000591150 uncertain significance Familial adenomatous polyposis 1 no assertion criteria provided clinical testing The APC p.Met1211Arg variant was not identified in the literature nor was it identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, COSMIC, MutDB, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, and UMD. The variant was submitted to the Clinvar database 1X by multiple submitters (INVITAE as uncertain significance, and ITMI, classification not provided). The p.Met1211 residue is not conserved in mammals and lower organisms, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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