Submissions for variant NM_020975.6(RET):c.3149G>A (p.Arg1050Gln)

gnomAD frequency: 0.00003  dbSNP: rs200956659

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225774	SCV000290559	uncertain significance	Multiple endocrine neoplasia, type 2	2025-02-03	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 1050 of the RET protein (p.Arg1050Gln). This variant is present in population databases (rs200956659, gnomAD 0.01%). This missense change has been observed in individual(s) with RET-related cancer (PMID: 30256826, 34663841, 35264596). ClinVar contains an entry for this variant (Variation ID: 241358). 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 disruptive. 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	RCV000563947	SCV000674849	likely benign	Hereditary cancer-predisposing syndrome	2021-08-09	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.
PreventionGenetics, part of Exact Sciences	RCV000679746	SCV000807048	uncertain significance	not provided	2016-12-30	criteria provided, single submitter	clinical testing
Mendelics	RCV003492013	SCV000838409	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196701	SCV001367332	uncertain significance	Multiple endocrine neoplasia type 2B	2019-10-17	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
GeneDx	RCV000679746	SCV001996342	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with colorectal, breast, and other cancers (PMID: 30256826, 34663841, 35264596); This variant is associated with the following publications: (PMID: 24336963, 14633923, 30256826, 34663841, 35264596)
Sema4, Sema4	RCV000563947	SCV002527902	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	curation
Baylor Genetics	RCV003463679	SCV004208705	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-03-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000225774	SCV004838719	uncertain significance	Multiple endocrine neoplasia, type 2	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1050 of the RET 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 an individual or family affected with Lynch syndrome (PMID: 30256826) and an individual affected with esophageal squamous cell carcinoma (PMID: 34663841). This variant has been identified in 9/282756 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.
Fulgent Genetics, Fulgent Genetics	RCV005044481	SCV005676694	likely benign	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2024-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055783	SCV005726060	uncertain significance	not specified	2024-11-21	criteria provided, single submitter	clinical testing	Variant summary: RET c.3149G>A (p.Arg1050Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3149G>A in individuals affected with Hirschsprung Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 241358). Based on the evidence outlined above, the variant was classified as uncertain significance.