ClinVar Miner

Submissions for variant NM_000038.6(APC):c.995G>A (p.Arg332Gln) (rs377665107)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167510 SCV000218368 likely benign Hereditary cancer-predisposing syndrome 2020-06-18 criteria provided, single submitter clinical testing Other data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV000200721 SCV000254053 uncertain significance Familial adenomatous polyposis 1 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 332 of the APC protein (p.Arg332Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs377665107, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 187754). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000480823 SCV000569143 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing This variant is denoted APC c.995G>A at the cDNA level, p.Arg332Gln (R332Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in a colorectal tumor that also harbored a truncating APC variant (Jesinghaus 2016). APC Arg332Gln was observed at an allele frequency of 0.012% (1/8628) in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Arg332Gln occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Arg332Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000167510 SCV000681942 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-22 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 332 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/282470 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.
Counsyl RCV000200721 SCV000785636 uncertain significance Familial adenomatous polyposis 1 2017-10-17 criteria provided, single submitter clinical testing

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