ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1901G>T (p.Cys634Phe) (rs75996173)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471652 SCV000543841 pathogenic Multiple endocrine neoplasia, type 2 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 634 of the RET protein (p.Cys634Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs75996173, ExAC 0.01%). This variant has been reported in the literature co-segregating with disease in several families (PMID: 8099202, 24716929, 24684035, 20739875, 17895320, 25628771) as well as present in multiple unrelated individuals affected with multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid cancer (MTC) (PMID: 16865647, 18062802, 25440022) and pheochromocytoma (PMID: 12000816). ClinVar contains an entry for this variant (Variation ID: 13911). This variant affects a highly conserved and functionally important cysteine amino acid residue of the RET protein. This residue is one of the most commonly altered codons in individuals affected with MEN2A (PMID: 8099202, 12000816, 21765987, 25440022). For these reasons, this variant has been classified as Pathogenic.
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
Research and Development, ARUP Laboratories RCV000471652 SCV000042491 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 7 yr. Youngest with Pheo: 26 yr (PMID 25629635). Patients may also have cutaneous lichen amyloidosis (PMID 7874109). In the oldest reference, codon 634 was called codon 380. Additional references: PMID 16712668, 11900218, 15452453, 12604374 and 11524247.

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