Submissions for variant NM_000038.6(APC):c.1691G>A (p.Arg564Gln)

gnomAD frequency: 0.00001  dbSNP: rs747418061

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213578	SCV000277820	likely benign	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004567640	SCV000647195	uncertain significance	Familial adenomatous polyposis 1	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 564 of the APC protein (p.Arg564Gln). This variant is present in population databases (rs747418061, gnomAD 0.03%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32068069). ClinVar contains an entry for this variant (Variation ID: 233448). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000213578	SCV000681484	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 564 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 32068069) and suspected of having Lynch syndrome (PMID: 25338684). This variant has been identified in 8/251308 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779711	SCV000916466	uncertain significance	not specified	2021-03-07	criteria provided, single submitter	clinical testing	Variant summary: APC c.1691G>A (p.Arg564Gln) results in a conservative amino acid change located in the Armadillo repeat of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1691G>A has been reported in the literature in individuals undergoing cancer multigene panel testing (example, Sapari_2014, Kwong_2020). These report(s) 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001572567	SCV001797230	uncertain significance	not provided	2023-04-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with breast and/or ovarian cancer (Kwong et al., 2020); This variant is associated with the following publications: (PMID: 25338684, 18199528, 32068069)
All of Us Research Program, National Institutes of Health	RCV003998557	SCV004837433	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 564 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 reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 32068069) and suspected of having Lynch syndrome (PMID: 25338684). This variant has been identified in 8/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in control individuals (PMID: 32980694). 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.
Baylor Genetics	RCV004567640	SCV005052141	uncertain significance	Familial adenomatous polyposis 1	2024-03-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV003998557	SCV005917849	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-10-09	criteria provided, single submitter	clinical testing