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 2018-12-14 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 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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 RCV000082052 SCV000886052 likely pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing The RET c.1998G>T;p.Lys666Asn variant (rs146646971) has been published in the medical literature in individuals and families with clinical diagnoses of medullary thyroid carcinoma (Muzza 2010, Xu 2016) and has been implicated as a low penetrance variant (Xu 2016). Additionally, other variants in this codon, p.Lys666Glu, p.Lys666Arg, and p.Lys666Met, have all been reported in the medical literature in association with RET-related disorders (Ahmed 2005, Borrello 2011, Mastroianno 2011, Wells 2015, Yamazaki 2014). The variant is listed in the ClinVar database (Variation ID: 24932) and observed in the general population database at a frequency of 0.0461 percent (6/13000 alleles) in the Exome Variant Server and 0.002170 percent (6/276472 alleles) in the Genome Aggregation Database. This amino acid is located in the intracellular juxtamembrane region in exon 11, downstream of the transmembrane domain, the amino acid at this position is highly conserved across species, and computational algorithms (AlignGVGD, PolyPhen2, SIFT, MutationTaster) predict this variant will impact the protein. In experiments carried out in cell culture, the variant protein shows high kinase activity and increased transforming activity (Muzza 2010). Considering all available information, this variant is considered likely 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 May;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 Jul 25;18(4):519-27. Mastroianno S et al. Coexistence of multiple endocrine neoplasia type 1 and type 2 in a large Italian family. Endocrine. 2011 Dec;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 Apr;162(4):771-7. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. Xu JY et al. Medullary Thyroid Carcinoma Associated with Germline RETK666N Mutation. Thyroid. 2016 Dec;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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000467461 SCV000966948 likely pathogenic Multiple endocrine neoplasia, type 2 2018-04-02 criteria provided, single submitter clinical testing The p.Ly666Asn variant in RET has been reported in 9 individuals with medullary thyroid carcinoma and segregated with disease in 1 affected relative from 1 fami ly (Muzza 2010, Xu 2016). This variant has been identified in 3/66676 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut; dbSNP rs146646971). Computational prediction tools and conservation analy sis suggest that the p.Ly666Asn variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Ly666Asn variant may impact thge prote in in a gain-of-function manner (Muzza 2010). However, these types of assays may not accurately represent biological function. In summary, although additional s tudies are required to fully establish its clinical significance, the p.Ly666Asn variant is likely pathogenic. ACMG criteria applied: PS4_Moderate; PM2; PS3_M oderate; PP3; PP4.
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).
CSER_CC_NCGL; University of Washington Medical Center RCV000148772 SCV000190509 likely benign Medullary thyroid carcinoma 2014-06-01 no assertion criteria provided research
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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