ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2556C>G (p.Ile852Met) (rs377767426)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204335 SCV000261072 uncertain significance Multiple endocrine neoplasia, type 2 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 852 of the RET protein (p.Ile852Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs377767426, ExAC 0.04%). This variant has been observed in several individuals affected with medullary thyroid cancer and non-small cell lung cancer (PMID: 11295841, 21711375, 28578594, 26556299, 27525386). Additionally, this variant has been observed in an individual affected with multiple endocrine neoplasia type 2 (MEN2A) (PMID: 24745698) and has been reported to co-segregate with a pathogenic RET variant in a family with MEN2A (PMID: 26876062). ClinVar contains an entry for this variant (Variation ID: 24955). Experimental studies have shown that this missense change may increase RET kinase activity in vitro (PMID: 21711375). 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 RCV000566408 SCV000674738 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Conflicting evidence
Counsyl RCV000662415 SCV000784850 uncertain significance Multiple endocrine neoplasia, type 2a 2017-01-16 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755693 SCV000883124 uncertain significance Multiple endocrine neoplasia, type 2b 2018-11-21 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000021869 SCV000042535 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only First report: single family, 2 have the mutation: 1 MTC at 20 yr. Second report (database submission): single individual with MTC at 65 yr. Third report: single family, five have the mutation: 1 MTC at 64 yr. Two recent reports indicate that p.I852M is likely a rare polymorphism, likely benign (PMID 28578594 and 29656518). For example, in a single Dutch family, three have the mutation: 1 MTC at 69 yr, 2 with C-cell hyperplasia at 39 and 42 yr. The MTC had a somatic RET mutation that was likely responsible for the cancer development versus the germline p.I852M mutation (PMID 28578594). Present in GnomAD at 0.017%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731). In vitro studies indicate weakly activating mutation: PMID 21711375. Has been found with another RET change, see c.[1901G>A;2556C>G].

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