Submissions for variant NM_020975.6(RET):c.2304G>C (p.Glu768Asp)

dbSNP: rs78014899

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001015022	SCV001175806	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-03	criteria provided, single submitter	clinical testing	The p.E768D pathogenic mutation (also known as c.2304G>C), located in coding exon 13 of the RET gene, results from a G to C substitution at nucleotide position 2304. The glutamic acid at codon 768 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported to segregate with disease in several patients and families with medullary thyroid cancer and has been observed in two patients with a clinical diagnosis of MEN2A (Boccia LM et al. Clin. Genet. 1997 Feb;51:81-5; Eng C et al. Oncogene. 1995 Feb;10:509-13; Aiello A et al. Surgery. 2005 May;137:574-6; Antiñolo G et al. Am. J. Med. Genet. 2002 Jun;110:85-7; Bolino A et al. Oncogene. 1995 Jun;10:2415-9; Machens A et al. Hum. Mutat. 2018 06;39(6):860-869; Ambry internal data). In multiple assays testing RET function, this variant showed a modest level of RET activation and transforming capabilities when compared to wildtype (Pasini A et al. Oncogene, 1997 Jul;15:393-402; Arighi E et al. Mol Endocrinol. 2004 Apr;18:1004-17). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unlikely.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021842	SCV001226408	pathogenic	Multiple endocrine neoplasia, type 2	2023-08-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 14715928, 15184865, 17047083, 26046350). 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 13931). This missense change has been observed in individuals with medullary thyroid carcinoma (PMID: 9263528, 11230481, 12116277, 15855933, 16736292, 17097365, 18062802; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 768 of the RET protein (p.Glu768Asp).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811141	SCV001474222	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing	The RET c.2304G>C; p.Glu768Asp variant (rs78014899) has been described in multiple individuals with medullary thyroid carcinoma (MTC; Aiello 2005, Eng 1995). This variant is reported in ClinVar (Variation ID: 13931) but is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 768 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, another variant resulting in the same amino acid change at this codon (c.2304G>T; p.Glu768Asp) has been described in individuals with MTC (Antinolo 2002, Millar 2011, Wiench 2001). In vitro functional studies of this variant indicate higher transforming capabilities when compared to wildtype (Pasini 1997). Based on available information, the p.Glu768Asp variant is considered pathogenic. REFERENCES Aiello A et al. The familial medullary thyroid carcinoma-associated RET E768D mutation in a multiple endocrine neoplasia type 2A case. Surgery. 2005 May;137(5):574-6. Antinolo G et al. A novel germline point mutation, c.2304 G-->T, in codon 768 of the RET proto-oncogene in a patient with medullary thyroid carcinoma. Am J Med Genet. 2002 Jun 1;110(1):85-7. Eng C et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995 Feb 2;10(3):509-13. Millar S et al. Familial pediatric endocrine tumors. Oncologist. 2011;16(10):1388-96. Pasini A et al. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene. 1997 Jul 24;15(4):393-402. Wiench M et al. Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol. 2001 Mar 1;19(5):1374-80.
OMIM	RCV000014956	SCV000035212	pathogenic	Familial medullary thyroid carcinoma	2002-06-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431893	SCV000505642	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439063	SCV000505643	likely pathogenic	Multiple endocrine neoplasia type 4	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421871	SCV000505644	likely pathogenic	Medullary thyroid carcinoma	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432579	SCV000505645	likely pathogenic	Multiple endocrine neoplasia type 2A	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445341	SCV000505646	likely pathogenic	Multiple endocrine neoplasia, type 1	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426010	SCV000505647	likely pathogenic	Multiple endocrine neoplasia type 2B	2016-05-13	no assertion criteria provided	literature only
CZECANCA consortium	RCV002280861	SCV002569172	likely pathogenic	Hepatocellular carcinoma	2022-05-17	no assertion criteria provided	case-control