Submissions for variant NM_020975.6(RET):c.2410G>C (p.Val804Leu)

dbSNP: rs79658334

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479688	SCV000565490	pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: increased transforming activity and autophosphorylation ability (Carlomagno et al., 2004; Iwashita et al., 1999; Pasini et al., 1997); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9879991, 10445857, 16532227, 11114642, 14718397, 9384613, 26247112, 20516206, 16865647, 10235148, 23705946, 18322301, 9242375, 15741265, 20497437, 16343097, 26269449, 25810047, 7784092, 18058472, 14633923, 11932300, 15184865, 30763276)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021853	SCV001219977	pathogenic	Multiple endocrine neoplasia, type 2	2023-07-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val804 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7784092, 10235148, 15741265, 16343097, 18058472, 26269449). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 38613). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2 (PMID: 7784092, 10235148, 14718397, 15741265, 16343097, 18058472, 26269449). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 804 of the RET protein (p.Val804Leu).
CeGaT Center for Human Genetics Tuebingen	RCV000479688	SCV001500904	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453279	SCV002736148	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-21	criteria provided, single submitter	clinical testing	The p.V804L pathogenic mutation (also known as c.2410G>C), located in coding exon 14 of the RET gene, results from a G to C substitution at nucleotide position 2410. The valine at codon 804 is replaced by leucine, an amino acid with highly similar properties. This alteration occurs in the ATP binding pocket of the tyrosine-kinase domain of the RET receptor, and has been reported as a pathogenic mutation associated with both FMTC and MEN2A (Bolino A et al. Oncogene, 1995 Jun;10:2415-9; Frohnauer MK et al. Surgery, 2000 Dec;128:1052-7;discussion 1057-8; Learoyd DL et al. Clin. Endocrinol. (Oxf), 2005 Dec;63:636-41; Maciel RMB et al. Endocr Connect, 2019 03;8:289-298). Functional studies demonstrate that p.V804L transfected cells exhibit an increase in the level of tyrosine phosphorylation compared to wildtype in one RET isoform, supporting its oncogenic potential (Pasini A et al. Oncogene 1997 Jul;15(4):393-402). In addition, expression studies demonstrate that p.V804L has a low transforming activity compared to other RET mutations. Transforming activity is associated with clinical phenotype; mutations with low transforming activity are associated with a milder MEN2/FMTC phenotype compared to mutations with high transforming activity that are associated with a more severe MEN2B phenotype (Iwashita T et al. Oncogene 1999 Jul;18(26):3919-22). The American Thyroid Association has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells SA et al. Thyroid. 2015 Jun;25(6):567-610; Kloos et al. Thyroid. 2009 June; 19(6):565-612). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226171	SCV003923158	pathogenic	MEN2 phenotype: Unclassified	2023-03-06	criteria provided, single submitter	clinical testing	Variant summary: RET c.2410G>C (p.Val804Leu) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 232600 control chromosomes (gnomAD). c.2410G>C has been reported in the literature in multiple individuals affected with Medullary Thyroid Carcinoma and Multiple Endocrine Neoplasia (example: Lombardo_2002, Paszko_2007, and Maciel_2019). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000021853	SCV004839086	likely pathogenic	Multiple endocrine neoplasia, type 2	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 804 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant resulted in intermediate level of transforming activity on ex vivo transfected cells (PMID: 9242375, 10445857) and to confer resistance to select kinase inhibitors (PMID: 26046350). This variant has been reported in three individuals affected with endocrine neoplasias and two related individuals affected with medullary thyroid cancer (PMID: 11114642, 28946813). Different variants occurring at the same codon, c.2410G>A (p.Val804Met) and c.2410G>T (p.Val804Leu), are well-documented pathogenic mutations (ClinVar variation ID: 37102, 13946), indicating that valine at this position is important for RET protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000426266	SCV004930973	pathogenic	Multiple endocrine neoplasia type 2A	2024-03-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9242375]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20497437, 16343097, 11932300, 25810047].
Database of Curated Mutations (DoCM)	RCV000425568	SCV000510542	likely pathogenic	Multiple endocrine neoplasia type 2B	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437130	SCV000510543	likely pathogenic	Multiple endocrine neoplasia type 4	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419916	SCV000510544	likely pathogenic	Multiple endocrine neoplasia, type 1	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426266	SCV000510545	likely pathogenic	Multiple endocrine neoplasia type 2A	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436948	SCV000510546	likely pathogenic	Medullary thyroid carcinoma	2016-05-13	no assertion criteria provided	literature only