ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2348A>C (p.Asn783Thr) (rs587778656)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724767 SCV000225909 uncertain significance not provided 2015-05-12 criteria provided, single submitter clinical testing
Counsyl RCV000412123 SCV000489829 uncertain significance Multiple endocrine neoplasia, type 2b 2016-05-12 criteria provided, single submitter clinical testing
Counsyl RCV000410090 SCV000489830 uncertain significance Multiple endocrine neoplasia, type 2a 2016-05-12 criteria provided, single submitter clinical testing
Invitae RCV000540063 SCV000658443 uncertain significance Multiple endocrine neoplasia, type 2 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 783 of the RET protein (p.Asn783Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is present in population databases (rs587778656, ExAC 0.002%). This variant has not been reported in the literature in individuals with RET-related disease. ClinVar contains an entry for this variant (Variation ID: 135178). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000561957 SCV000674763 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000724767 SCV000886057 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing The RET c.2348A>C; p.Asn783Thr variant (rs587778656), to our knowledge, has not been described in the medical literature but has been reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 135178) and is observed in the general population at a low overall frequency of 0.002% (5/246198 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (c.2348A>G; p.Asn783Ser) has been detected in individuals affected with Hirschsprung disease and medullary thyroid cancer (Lebeault 2017, So 2011). The asparagine at codon 783 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict that this variant is deleterious. However, due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Lebeault M et al. Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers. Thyroid. 2017 Dec;27(12):1511-1522. So M et al. RET Mutational Spectrum in Hirschsprung Disease: Evaluation of 601 Chinese Patients. PLoS One. 2011; 6(12): e28986.
Mendelics RCV000410090 SCV001138031 uncertain significance Multiple endocrine neoplasia, type 2a 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000121980 SCV000086190 not provided not specified 2013-09-19 no assertion provided reference population

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