Submissions for variant NM_000038.6(APC):c.6965A>G (p.Gln2322Arg)

gnomAD frequency: 0.00001  dbSNP: rs1057517549

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410185	SCV000488227	uncertain significance	Familial adenomatous polyposis 1	2016-01-28	criteria provided, single submitter	clinical testing
Invitae	RCV000410185	SCV000647681	likely benign	Familial adenomatous polyposis 1	2023-11-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580861	SCV000681840	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 2322 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in trans with an individual with a whole-gene deletion of the APC gene with familial adenomatous polyposis phenotypes (PMID: 22799487) and an individual not selected for cancer or polyposis phenotypes (PMID: 28706299). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics	RCV000410185	SCV000838145	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580861	SCV001188118	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194172	SCV001363504	uncertain significance	not specified	2019-03-26	criteria provided, single submitter	clinical testing	Variant summary: APC c.6965A>G (p.Gln2322Arg) results in a conservative amino acid change located in the Adenomatous polyposis coli protein basic domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245592 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6965A>G has been reported in the literature in an apparent homzygote individual suspected FAP and had a strong family history of cancer. The patient was found to also carry a large 5.2 Mb deletion that encompassed the APC gene and 19 additional genes. Four ClinVar submissions from clinical diagnostic laboratories and/or reputable databases (evaluation after 2014) cite the variant three times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV001575254	SCV001802211	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22799487)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001575254	SCV002774415	uncertain significance	not provided	2021-08-12	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410185	SCV004018330	uncertain significance	Familial adenomatous polyposis 1	2023-02-14	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.