Submissions for variant NM_020975.6(RET):c.1891G>A (p.Asp631Asn)

gnomAD frequency: 0.00004  dbSNP: rs377767406

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519407	SCV000618423	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate absent transforming activity and no independent dimerization (PMID: 10049754); This variant is associated with the following publications: (PMID: 23264394, 26639839, 21479187, 25810047, 14633923, 10049754, 30927507, 35534704)
Ambry Genetics	RCV000564566	SCV000674829	likely benign	Hereditary cancer-predisposing syndrome	2021-11-29	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	RCV000696792	SCV000825371	uncertain significance	Multiple endocrine neoplasia, type 2	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 631 of the RET protein (p.Asp631Asn). This variant is present in population databases (rs377767406, gnomAD 0.03%). This missense change has been observed in individual(s) with RET-related conditions (PMID: 30927507, 35534704). ClinVar contains an entry for this variant (Variation ID: 24913). 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. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 10049754). This variant disrupts the p.Asp631 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10049754, 16839264, 22274720). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics	RCV002477000	SCV000896058	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-04-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818172	SCV002071196	uncertain significance	not specified	2019-09-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460488	SCV004206713	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-06-22	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004786279	SCV005402301	uncertain significance	Multiple endocrine neoplasia type 2A	2024-03-15	criteria provided, single submitter	clinical testing	The RET c.1891G>A (p.Asp631Asn) missense change has a maximum subpopulation frequency of 0.04% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant has been reported in the literature in an individual with medullary thyroid cancer (PMID: 30927507). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV004786279	SCV005403696	likely benign	Multiple endocrine neoplasia type 2A	2024-08-09	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.