Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000471652 | SCV000543841 | pathogenic | Multiple endocrine neoplasia, type 2 | 2023-10-31 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Phe). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individuals with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid cancer (MTC) and/or pheochromocytoma (PMID: 8099202, 12000816, 16865647, 17895320, 18062802, 20739875, 24684035, 24716929, 25440022, 25628771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13911). 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. This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8099202, 12000816, 21765987, 25440022). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Institute for Clinical Genetics, |
RCV003237413 | SCV002011457 | pathogenic | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002408463 | SCV002718170 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-12-06 | criteria provided, single submitter | clinical testing | The p.C634F pathogenic mutation (also known as c.1901G>T), located in coding exon 11 of the RET gene, results from a G to T substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This mutation has been identified in multiple individuals meeting clinical diagnostic criteria for multiple endocrine neoplasia type 2A (MEN2A) and has been demonstrated to segregate with disease within several MEN2A families (Saito T et al. Am J Med Sci. 2010 Oct;340(4):329-31; Jesic M et al. Srp Arh Celok Lek. 2014 Jan-Feb;142(1-2):72-4; Masbi H et al. Asian Pac J Cancer Prev. 2014;15(5):2027-33; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). This mutation occurs at a known hotspot and studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002; 346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003; 138:409-16). Per the American Thyroid Association Guideline Taskforce of 2009 (ATA), this mutation has screening and prophylactic recommended interventions beginning in early childhood. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
KCCC/NGS Laboratory, |
RCV000014928 | SCV003927262 | pathogenic | Multiple endocrine neoplasia type 2A | 2023-05-31 | criteria provided, single submitter | clinical testing | phenylalanine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Phe). This variant is present in population databases (rs75996173, gnomAD 0.007%). This misscnse change has been observed in individuals with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid cancer (MTC) and7or phcochromocytoma (PMID: 8099202, 12000816, 16865647, 17895320, 18062802, 20739875, 24684035, 24716929, 25440022, 25628771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13911). Algorithms developed to predict the effect of misscnse changes on protein structure and function are either unavailable or do not agree on the potential impact of this misscnse change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class CO"). This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8099202, 12000816, 21765987, 25440022). For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the RET gene are associated with multiple endocrine neoplasia type 2. |
Institute of Human Genetics, |
RCV000014928 | SCV004698061 | pathogenic | Multiple endocrine neoplasia type 2A | 2024-02-14 | criteria provided, single submitter | clinical testing | Criteria applied: PS4,PM5_STR,PM1,PM2_SUP,PP3 |
Mayo Clinic Laboratories, |
RCV003237413 | SCV005413943 | pathogenic | not provided | 2022-03-10 | criteria provided, single submitter | clinical testing | PP3, PP4, PP5, PM2_moderate, PM5 |
OMIM | RCV000014928 | SCV000035184 | pathogenic | Multiple endocrine neoplasia type 2A | 2002-05-09 | no assertion criteria provided | literature only | |
OMIM | RCV000014929 | SCV000035185 | pathogenic | Familial medullary thyroid carcinoma | 2002-05-09 | no assertion criteria provided | literature only | |
OMIM | RCV000014930 | SCV000035186 | pathogenic | Pheochromocytoma | 2002-05-09 | no assertion criteria provided | literature only |