ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2370G>T (p.Leu790Phe) (rs75030001)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163610 SCV000214175 pathogenic Hereditary cancer-predisposing syndrome 2018-04-27 criteria provided, single submitter clinical testing Good segregation with disease (lod 1.5-3 = 5-9 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;Significant disease association in appropriately sized case-control study(ies)
GeneDx RCV000339507 SCV000329491 pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.2370G>T at the cDNA level, p.Leu790Phe (L790F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTT). This variant has been observed in several individuals with Familial Medullary Thyroid Cancer (FMTC) as well as in individuals with pheochromocytoma (Rodien 1997, Berndt 1998, Fitze 2002, Gimm 2002, Bihan 2012, Min 2012, Pirich 2012, Wang 2016). Additionally, it was shown to co-segregate with disease in two large families (Berndt 1998, Bihan 2012). RET Leu790Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the tyrosine kinase domain (Garcia-Barcelo 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000539138 SCV000658446 pathogenic Multiple endocrine neoplasia, type 2 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 790 of the RET protein (p.Leu790Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs75030001, ExAC 0.01%). This variant has been reported to segregate with medullary thyroid carcinoma in multiple families (PMID: 9506724, 23756355, 21688339, 12409662, 22965292), and has been observed in individuals with pheochromocytoma (PMID: 22403753, 9506724). Notably, the p.Leu790Phe variant is associated with a less aggressive form of multiple endocrine neoplasia type 2, with fewer cases of pheochromocytoma compared to other pathogenic RET variants (PMID: 23756355, 21688339, 12490841). ClinVar contains an entry for this variant (Variation ID: 38612). A different variant (c.2370G>C) giving rise to the same protein effect observed here (p.Leu790Phe) has also been reported in multiple families affected with medullary thyroid carcinoma (PMID: 9506724, 23756355, 21688339, 12490841), indicating that this residue may be critical for protein function. Experimental studies have shown that the cell growth activity of this missense variant is similar to the wild-type. However, this variant may impact a function that was not assessed by this study (PMID: 21810974). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709758 SCV000840057 pathogenic Multiple endocrine neoplasia, type 2a 2017-04-04 criteria provided, single submitter clinical testing The c.2370G>C (p.Leu790Phe) variant has been reported in patients with familial and sporadic medullary thyroid cancer [PMID 9506724, 22965292, 21810974] and pheochromocytoma [PMID 22403753]. Segregation of the variant with medullary thyroid carcinoma was reported in several families [PMID 9506724, 22965292]. Another variant affecting the same amino acid at position 790 (c.2370G>T) and leading to the same amino acid change (p.Leu790Phe) has also been reported in patients with sporadic medullary thyroid cancer and pheochromocytoma [PMID 9506724]. A retrospective study showed that patients carrier for this p.Leu790Phe change have a non-aggressive form or slow evolving multiple endocrine neoplasia type 2 [PMID 23756355]. The role of prophylactic thyroidectomy in patients carriers for this p.Leu790Phe variant was also evaluated [PMID 21688339]. Two carriers from this study were over 70 years of age and were asymptomatic. Thus, the authors concluded that, for carriers of this p.Leu790Phe variant, a case-by-case decision instead of systematic prophylactic thyroidectomy should be discussed [PMID 21688339]. This variant was observed in two individuals at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/10-43613906-G-T).This variant is highly conserved in mammals and while not clinically validated, computer-based algorithms predict this p.Leu790Phe change to be deleterious. This variant is thus classified as pathogenic. This variant is also considered medically actionable [ACMG 59, PMID 27854360].
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999913 SCV000886053 pathogenic not specified 2019-01-11 criteria provided, single submitter clinical testing The RET c.2370G>T, p.Leu790Phe variant (rs75030001) has been reported in multiple individuals and families with medullary thyroid carcinoma (MTC; Berndt 1998, Bihan 2013, Fitze 2002) and in individuals with pheochromocytoma (Berndt 1998, Min 2012). This variant is listed as pathogenic in ClinVar (Variation ID: 38612), and observed in the general population at a low overall frequency of 0.002% (5/251150 alleles) in the Genome Aggregation Database. The leucine at codon 790 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, another variant that results in the same amino acid change (c.2370G>C; p.Leu790Phe) has been reported in individuals affected with MTC (Berndt 1998). Based on available information, the c.2370G>T variant is considered pathogenic. REFERENCES Berndt I et al. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. 1998;J Clin Endocrinol Metab. 83(3):770-4. Bihan H et al. The clinical spectrum of RET proto-oncogene mutations in codon 790. 2013;Eur J Endocrinol. 169(3):271-6. Fitze G et al. Various penetrance of familial medullary thyroid carcinoma in patients with RET protooncogene codon 790/791 germline mutations. Ann Surg. 2002 Nov;236(5):570-5. Min J et al. Bilateral adrenal pheochromocytoma with a germline L790F mutation in the RET oncogene. J Korean Surg Soc. 2012 Mar;82(3):185-9.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000984325 SCV001132523 pathogenic Familial medullary thyroid carcinoma 2018-01-16 criteria provided, single submitter curation
Institute of Human Genetics, University of Leipzig Medical Center RCV000709758 SCV001428939 uncertain significance Multiple endocrine neoplasia, type 2a 2017-09-29 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000539138 SCV000055391 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 16 yr (PMID 16865646). Youngest with Pheo: 28yr. Additional references: PMID 12409662, 12193298, 12490841 and 18062802. Has been found with another RET change, see c.1807 A>C(;)2370 G>T.

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