ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1998G>T (p.Lys666Asn) (rs146646971)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082052 SCV000225404 pathogenic not provided 2013-04-23 criteria provided, single submitter clinical testing
GeneDx RCV000082052 SCV000329490 pathogenic not provided 2018-07-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.1998G>T at the cDNA level, p.Lys666Asn (K666N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAT). This variant was observed in individuals diagnosed with medullary thyroid cancer (Muzza 2010, Boichard 2012, Xu 2016). This variant was found to segregate with medullary thyroid cancer, C-cell hyperplasia and/or elevated calcitonin in multiple families; however, several carriers were identified in these families that did not show evidence of disease, suggesting that this may be a low penetrance allele (Xu 2016). In functional studies by Muzza et al. (2010), this variant displayed increased tyrosine phosphorylation activity, kinase activity, and transforming potential compared to wild-type. RET Lys666Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. RET Lys666Asn is located in the intracellular domain (Garcia-Barcel? 2004). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000467461 SCV000543812 pathogenic Multiple endocrine neoplasia, type 2 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 666 of the RET protein (p.Lys666Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs146646971, ExAC 0.004%). This variant has been reported in several individuals affected with medullary thyroid cancer (MTC) (PMID: 20103606, 27673361) and segregates with disease in families (PMID: 27673361, Invitae). This variant was also carried by unaffected family members, suggesting that it may be associated with a relatively low penetrance of disease. ClinVar contains an entry for this variant (Variation ID: 24932). Experimental studies have shown that this missense change results in a significant increase of ERK and RET phosphorylation and cellular transformation (PMID: 20103606). A c.1998G>C variant giving rise to the same protein effect observed here (p.Lys666Asn) (PMID: 26269449), and different missense variants affecting the same codon (p.Lys666Glu, p.Lys666Met and p.Lys666Arg) (PMID: 15858153, 21690267, 24569963, 21678021, 25319874) have been reported in affected individuals, suggesting that the lysine residue is critical for RET protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000570730 SCV000674739 pathogenic Hereditary cancer-predisposing syndrome 2018-11-09 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position;Structural Evidence;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000174156 SCV000840058 likely pathogenic Multiple endocrine neoplasia, type 2a 2018-04-25 criteria provided, single submitter clinical testing This c.1998G>G (p.Lys666Asn) variant in the RET gene has been reported in eight families with familial medullary thyroid carcinoma [PMID: 27673361]. This variant has also been reported in multiple clinical testing centers as disease-causing according to ClinVar while observed as extremely low in general population according to gnomad database. Functional studies showed this variant displays high kinase and transforming activities [PMID: 20103606]. Multiple in silico predictions suggest this lysine to asparagine is deleterious. Multiple disease-causing or risk associated variants have been reported to cause lysine at amino acid position 666 change to other amino acids in literatures[PMID: 15858153, 25319874, 25810047] and/or in ClinVar database. Based upon above evidences, c.1998G>G (p.Lys666Asn) variant in the RET gene is classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999912 SCV000886052 pathogenic not specified 2018-11-06 criteria provided, single submitter clinical testing The RET c.1998G>T; p.Lys666Asn variant (rs146646971), is reported in the literature in individuals and families affected with medullary thyroid carcinoma and pheochromocytoma as a low penetetrance variant (Jaber 2018, Lebeault 2017, Muzza 2010, Xu 2016, Yehia 2018). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 24932), and is found in the non-Finnish European population with an allele frequency of 0.0054% (7/129,112 alleles) in the Genome Aggregation Database. Additionally, other amino acid substitutions at this codon (Glu, Arg, Met), as well as another variant at the same nucleotide (c.1998G>C; p.Lys666Asn), have been reported in individuals with RET-related disorders and are considered pathogenic/likely pathogenic (Ahmed 2005, Borrello 2011, Curras-Freixes 2015, Lebeault 2017, Mastroianno 2011, Wells 2015, Yamazaki 2014). The lysine at codon 666 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the p.Lys666Asn variant protein show increased kinase and transforming activity (Muzza 2010). Based on available information, the p.Lys666Asn variant is considered to be pathogenic. References: Ahmed SA et al. Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases. J Mol Diagn. 2005; 7(2):283-8. Borrello MG et al. Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism. Endocr Relat Cancer. 2011; 18(4):519-27. Curras-Freixes M et al. Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. J Med Genet. 2015 Oct;52(10):647-56. Jaber T et al. A Homozygous RET K666N Genotype With an MEN2A Phenotype. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1269-1272. Lebeault M et al. Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers. Thyroid. 2017 Dec;27(12):1511-1522. Mastroianno S et al. Coexistence of multiple endocrine neoplasia type 1 and type 2 in a large Italian family. Endocrine. 2011; 40(3):481-5. Muzza M et al. Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro. Eur J Endocrinol. 2010; 162(4):771-7. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6):567-610. Xu JY et al. Medullary Thyroid Carcinoma Associated with Germline RETK666N Mutation. Thyroid. 2016; 26(12):1744-1751. Yamazaki M et al. A newly identified missense mutation in RET codon 666 is associated with the development of medullary thyroid carcinoma. Endocr J. 2014; 61(11):1141-4. Yehia L et al. Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. PLoS Genet. 2018 Apr 23;14(4):e1007352.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000467461 SCV000966948 pathogenic Multiple endocrine neoplasia, type 2 2019-10-23 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001027731 SCV001190322 likely pathogenic Familial medullary thyroid carcinoma 2019-10-31 criteria provided, single submitter research
Research and Development, ARUP Laboratories RCV000467461 SCV000042505 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only Variant is likely pathogenic and associated with low disease penetrance. First report: French individual with MTC only at 65 yr. Second report: French individual with MTC only at 59 yr (PMID 28946813). Third report: single family, 6 with mutation: 2 MTC (55 yr, 70 yr). Seven unrelated individual cases with mutation and MTC at 22, 23, 33, 49, 51, 59, or 64 yr. Two of these individuals had a second RET change c.2608-24G>A (benign) or p.V412M (uncertain). Two cases were multifocal MTC, and all were negative for Pheo and HPT screening (PMID 27673361). Fourth report: single individual with MTC and HPT at 54 yr ( abstract P16). Fifth report: single family, 5 with heterozygous p.K666N mutation: 1 MTC (32 yr), 1 CCH (30 yr), and 3 are asymptomatic (25, 43, and 61yr), PMID 29408964. In this family, p.K666N was also found as homozygous in 1 family member (see our other c.1998G>T entry).
Research and Development, ARUP Laboratories RCV000174156 SCV000788302 pathogenic Multiple endocrine neoplasia, type 2a 2018-05-04 no assertion criteria provided literature only Single family report: 1 with MTC and bi-lateral Pheo (58 yr) was homozygous for p.K666N, genotype c.1998[G>T];[G>T]. Five additional family members were only heterozygous for the mutation: 1 MTC (32 yr), 1 CCH (30 yr), and 3 are asymptomatic (25, 43, and 61yr).

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