Submissions for variant NM_020975.6(RET):c.1996A>G (p.Lys666Glu)

gnomAD frequency: 0.00001  dbSNP: rs143795581

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567780	SCV000674767	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The p.K666E pathogenic mutation (also known as c.1996A>G), located in coding exon 11 of the RET gene, results from an A to G substitution at nucleotide position 1996. The lysine at codon 666 is replaced by glutamic acid, an amino acid with similar properties. This mutation has been identified in three unrelated families with medullary thyroid cancer. In one family, 12 individuals were tested, and the mutation was observed to segregate with disease in 6/6 affected individuals (Ahmed SA et al. J Mol Diagn 2005;7:283-8). In an in vitro focus formation assay, the mutant protein demonstrated transforming activity and oncogenic potential at levels higher than wild type, but lower than the well-described pathogenic p.C634R mutation (Borrello MG et al. Endocr. Relat. Cancer 2011; 18:519-27). Another pathogenic alteration at this codon (p.K666N) has been described in a female with sporadic medullary thyroid cancer and was also observed to have increased oncogenic potential compared to the wild type (Muzza M et al. Eur J Endocrinol. 2010 Apr;162(4):771-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021838	SCV000834776	pathogenic	Multiple endocrine neoplasia, type 2	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 666 of the RET protein (p.Lys666Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid cancer and pheochromocytoma (PMID: 15858153, 21690267, 30927507). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24931). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 21690267). This variant disrupts the p.Lys666 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20103606, 26269449, 27673361). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001582493	SCV001820626	likely pathogenic	not provided	2024-09-18	criteria provided, single submitter	clinical testing	Categorized as a moderate risk allele for aggressive medullary thyroid carcinoma by the American Thyroid Association (PMID: 25810047); Published functional studies demonstrate increased transforming activity and ERK phosphorylation (PMID: 21690267); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 20103606, 27673361, 29590403, 29284153, 24699901, 25440022, 26732158, 29408964, 27809725, 26678667, 28740527, 15858153, 31510104, 32375120, 30927507, 37900832, 14633923, 32376047, 38339246, 26580448, 33340421, 37835559, 21690267, 25810047)
Sema4, Sema4	RCV000567780	SCV002529959	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-22	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV002466411	SCV002761509	likely pathogenic	Hirschsprung disease, susceptibility to, 1	2021-04-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496436	SCV002775917	pathogenic	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-02-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001582493	SCV004225282	likely pathogenic	not provided	2022-03-03	criteria provided, single submitter	clinical testing	PP1, PP5, PM2, PS3, PS4_moderate
All of Us Research Program, National Institutes of Health	RCV000021838	SCV004839347	likely pathogenic	Multiple endocrine neoplasia, type 2	2023-10-30	criteria provided, single submitter	clinical testing	Functional studies suggest that this variant has a deleterious effect on the protein (PMID: 21690267). This variant has been reported in multiple individuals with multiple endocrine neoplasia (PMID: 15858153, 21690267, 30927507, 31510104, 26580448). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Other missense substitutions at this amino acid residue have been previously reported in individual(s) with disease and classified as pathogenic, which supports the functional importance of this position. This variant has been reported to co-segregate with disease in affected individuals in one family (PMID: 15858153). This variant is predicted to be deleterious by in silico analysis.
Myriad Genetics, Inc.	RCV004018657	SCV004930768	likely pathogenic	Multiple endocrine neoplasia type 2A	2024-01-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15858153, 30927507, 21690267, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 21690267].
Baylor Genetics	RCV002466411	SCV005054219	pathogenic	Hirschsprung disease, susceptibility to, 1	2023-12-17	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148771	SCV000190508	likely benign	Medullary thyroid carcinoma	2014-06-01	no assertion criteria provided	research