Submissions for variant NM_020975.6(RET):c.1904G>A (p.Arg635His)

gnomAD frequency: 0.00001  dbSNP: rs776164321

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205542	SCV000260468	uncertain significance	Multiple endocrine neoplasia, type 2	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 635 of the RET protein (p.Arg635His). This variant is present in population databases (rs776164321, gnomAD 0.006%). 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: 220149). 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	RCV002408893	SCV002722009	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	The p.R635H variant (also known as c.1904G>A), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide position 1904. The arginine at codon 635 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485344	SCV002785767	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2024-06-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000205542	SCV004841294	uncertain significance	Multiple endocrine neoplasia, type 2	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 635 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 not been reported as germline mutations in individuals affected with autosomal-dominant RET-related cancer in the literature. This variant has been identified in 8/247664 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004786547	SCV005402302	uncertain significance	Multiple endocrine neoplasia type 2A	2024-03-22	criteria provided, single submitter	clinical testing	The RET c.1904G>A (p.Arg635His) missense change has a maximum subpopulation frequency of 0.006% 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, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. 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.