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

gnomAD frequency: 0.00006  dbSNP: rs575268622

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003650380	SCV000166031	likely benign	Familial adenomatous polyposis 1	2024-01-24	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	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.
Counsyl	RCV000122774	SCV000784915	uncertain significance	Familial adenomatous polyposis 1	2017-02-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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.
Sema4, Sema4	RCV000568279	SCV002533858	likely benign	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000122774	SCV004018774	likely benign	Familial adenomatous polyposis 1	2023-02-21	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.
PreventionGenetics, part of Exact Sciences	RCV003905137	SCV004732887	likely benign	APC-related condition	2020-02-04	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.