Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000688498 | SCV000816113 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2025-01-19 | 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 133 of the RET protein (p.Arg133His). This variant is present in population databases (rs138265837, gnomAD 0.05%). 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: 568215). 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 | RCV001021592 | SCV001183228 | benign | Hereditary cancer-predisposing syndrome | 2023-05-03 | criteria provided, single submitter | clinical testing | This alteration is classified as 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002469258 | SCV002766425 | likely benign | not specified | 2022-11-03 | criteria provided, single submitter | clinical testing | Variant summary: RET c.398G>A (p.Arg133His) results in a non-conservative amino acid change located in the cadherin like domain 1 (IPR041163) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251416 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database (exomes dataset). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 18-fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 (MEN2) phenotype (3.7e-05), and is about 2.75-fold of the estimated MPAF for causing Hirschsprung Disease (HD) phenotype (0.00025), suggesting that the variant is a benign polymorphism for both phenotypes. To our knowledge, no occurrence of c.398G>A in individuals affected with Multiple Endocrine Neoplasia Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. A different missense variant affecting the same residue (R133C), has been reported in an individual affected with Hirschsprung disease (HGMD). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
| Fulgent Genetics, |
RCV002485619 | SCV002791225 | uncertain significance | Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A | 2022-03-11 | criteria provided, single submitter | clinical testing | |
| Breakthrough Genomics, |
RCV004692095 | SCV005190709 | uncertain significance | not provided | criteria provided, single submitter | not provided |