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

dbSNP: rs587778656

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 783 of the RET protein (p.Asn783Thr). This variant is present in population databases (rs587778656, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 135178). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	likely benign	Hereditary cancer-predisposing syndrome	2023-05-27	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.
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
GeneDx	RCV000724767	SCV003929605	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923, 24728327)
Myriad Genetics, Inc.	RCV000410090	SCV004018081	likely benign	Multiple endocrine neoplasia, type 2a	2023-04-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
PreventionGenetics, part of Exact Sciences	RCV003390808	SCV004120368	uncertain significance	RET-related condition	2024-01-02	criteria provided, single submitter	clinical testing	The RET c.2348A>C variant is predicted to result in the amino acid substitution p.Asn783Thr. To our knowledge, this variant has not been reported in the literature in association with disease. This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135178/). An alternate variant at the same amino acid position has been reported in a patient with Hirschsprung disease (p.Asn783Ser; So et al. 2011. PubMed ID: 22174939). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003460859	SCV004206698	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-07-11	criteria provided, single submitter	clinical testing
ITMI	RCV000121980	SCV000086190	not provided	not specified	2013-09-19	no assertion provided	reference population