Submissions for variant NM_000038.6(APC):c.6639G>A (p.Met2213Ile)

gnomAD frequency: 0.00004  dbSNP: rs35540155

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130211	SCV000185049	likely benign	Hereditary cancer-predisposing syndrome	2021-04-02	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	RCV000409211	SCV000488876	uncertain significance	Familial adenomatous polyposis 1	2016-07-18	criteria provided, single submitter	clinical testing
Invitae	RCV003650393	SCV000552646	benign	Familial adenomatous polyposis 1	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000484737	SCV000566001	likely benign	not provided	2020-12-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 24123366, 21153778, 31159747)
GeneKor MSA	RCV000130211	SCV000821822	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765788	SCV000897177	uncertain significance	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130211	SCV000910766	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001157265	SCV001318816	uncertain significance	APC-Associated Polyposis Disorders	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222403	SCV002500145	uncertain significance	not specified	2023-11-13	criteria provided, single submitter	clinical testing	Variant summary: APC c.6639G>A (p.Met2213Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249670 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6639G>A has been reported in the literature in individuals individuals affected with breast /ovarian cancer or undergoing lynch syndrome testing without evidence for causality (examples: Yurgelun_2015 and Tsaousis_2019). 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. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 31159747). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUs (n=6) and benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000484737	SCV003826827	uncertain significance	not provided	2022-09-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409211	SCV004018775	uncertain significance	Familial adenomatous polyposis 1	2023-02-21	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.