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

dbSNP: rs79658334

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000354366	SCV000329834	pathogenic	not provided	2022-12-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: increased transforming activity and autophosphorylation (Carlomagno et al., 2004; Iwashita et al., 1999; Kodama et al., 2014; 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: 23811235, 7784092, 25637381, 23705946, 16507829, 26269449, 9067749, 23059849, 22162569, 15741265, 10235148, 9242375, 12694233, 20516206, 16532227, 27809725, 26678667, 16343097, 29590403, 31510104, 30624503, 33087929, 14633923, 26046350, 26247112, 11932300, 25349307, 15693160, 10445857, 15184865)
GenePathDx, GenePath diagnostics	RCV000487450	SCV000574540	pathogenic	Familial medullary thyroid carcinoma; Multiple endocrine neoplasia	2016-10-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000354366	SCV000605022	pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing	The RET c.2410G>T; p.Val804Leu variant (rs79658334) has been reported in multiple individuals with familial medullary thyroid carcinoma (Lesueur 2005, Lombardo 2002, Patocs 2003) and multiple endocrine neoplasia type 2A (Learoyd 2005, Patocs 2003), segregating with affected individuals in the families (Learoyd 2005, Lombardo 2002, Patocs 2003). However, this variant was also found in some unaffected carriers in the pedigree, suggesting that it may have incomplete penetrance (Lombardo 2002, Patocs 2003). Functional characterization of the variant protein indicates autophosphorylation and activation of the kinase in the absence of growth factors, resulting in the increased phosphorylation of downstream targets and aberrant cell proliferation (Iwashita 1991, Pasini 1997). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 13946), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 804 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, the p.Val804Leu variant is considered to be pathogenic. References: Iwashita T et al. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene. 1991; 18(26):3919-22. Learoyd D et al. Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf). 2005; 63(6):636-41. Lesueur F et al. Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab. 2005; 90(6):3454-7. Lombardo F et al. Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. J Clin Endocrinol Metab. 2002; 87(4):1674-80. Pasini A et al. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene. 1997; 15(4):393-402. Patocs A et al. Segregation of the V804L mutation and S836S polymorphism of exon 14 of the RET gene in an extended kindred with familial medullary thyroid cancer. Clin Genet. 2003; 63(3):219-23.
Ambry Genetics	RCV000561258	SCV000674843	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	clinical testing	The p.V804L pathogenic mutation (also known as c.2410G>T), located in coding exon 14 of the RET gene, results from a G to T 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 (Toledo SP et al. Clinics (Sao Paulo) 2006 Feb; 61(1):59-70; Raue F et al. Fam. Cancer 2010 Sep; 9(3):449-57). Additionally, this alteration was detected in conjunction with a second RET alteration, pVal648Ile, in another individual with features of MEN2A, including pheochromocytoma and medullary thyroid cancer (Verrienti A et al. Endocr Pract, 2015 Nov;21:1248-54). 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 Guidelines Task Force has provided recommendations for individuals with RET gene mutations (Kloos et al. Thyroid. 2009 June; 19(6):565-612). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Eurofins Ntd Llc (ga)	RCV000354366	SCV000705164	pathogenic	not provided	2017-01-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000596480	SCV000786135	pathogenic	Multiple endocrine neoplasia, type 2a	2018-03-02	criteria provided, single submitter	clinical testing
Invitae	RCV000021854	SCV000824152	pathogenic	Multiple endocrine neoplasia, type 2	2023-12-06	criteria provided, single submitter	clinical testing	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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with medullary thyroid carcinoma and/or pheochromocytoma (PMID: 7784092, 10235148, 15741265, 16343097, 18058472, 18062802, 19469690, 21626080, 25810047, 26269449). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13946). 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: 9242375, 16507829, 26046350). 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: 8797874, 9452077, 10876191). 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.
Athena Diagnostics Inc	RCV000354366	SCV000842755	pathogenic	not provided	2017-11-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000354366	SCV002020785	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000354366	SCV002522519	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PP5, PM1, PM2, PM5, PS3_supporting
Myriad Genetics, Inc.	RCV000596480	SCV004018495	pathogenic	Multiple endocrine neoplasia, type 2a	2023-04-18	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].
Color Diagnostics, LLC DBA Color Health	RCV000021854	SCV004357248	pathogenic	Multiple endocrine neoplasia, type 2	2023-04-18	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, 26046350). This variant has been reported in dozens of heterozygous individuals affected with medullary thyroid cancer (PMID: 7784092, 10235148, 11932300, 12694233, 15741265, 20516206, 21626080) and one homozygous carrier affected with medullary thyroid cancer and pheochromocytoma (PMID: 15741265). This variant is also reported to segregate with disease in multiple families (PMID: 10235148, 11932300). This variant is reported to confer moderate risk for medullary thyroid cancer (PMID: 25810047). This variant has been identified in 1/232600 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000014973	SCV000035229	pathogenic	Familial medullary thyroid carcinoma	2005-06-01	no assertion criteria provided	literature only