Submissions for variant NM_020975.6(RET):c.2370G>C (p.Leu790Phe)

dbSNP: rs75030001

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182583	SCV000234935	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate transforming activity similar to wildtype (PMID: 21810974); This variant is associated with the following publications: (PMID: 23756355, 21810974, 19469690, 22403753, 9167962, 14633923, 33167350, 20516206, 16314641, 28125078, 30355600, 9506724, 33827484, 17895320, 21054478, 29656518, 29590403, 28946813, 30624503, 12490841, 11238493, 25810047)
Counsyl	RCV000014960	SCV000784781	likely pathogenic	Multiple endocrine neoplasia type 2A	2017-12-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021849	SCV000934365	pathogenic	Multiple endocrine neoplasia, type 2	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 790 of the RET protein (p.Leu790Phe). This variant is present in population databases (rs75030001, gnomAD 0.0009%). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 9506724, 12409662, 12490841, 14561794, 16868135, 18062802, 20516206, 20833330, 21688339, 22965292, 23756355, 25767701). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13935). 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 does not substantially affect RET function (PMID: 21810974). For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000014961	SCV002556878	pathogenic	Familial medullary thyroid carcinoma	2021-10-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000014961	SCV002580641	likely pathogenic	Familial medullary thyroid carcinoma	2022-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453262	SCV002735867	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-30	criteria provided, single submitter	clinical testing	The p.L790F pathogenic mutation (also known as c.2370G>C), located in coding exon 13 of the RET gene, results from a G to C substitution at nucleotide position 2370. The leucine at codon 790 is replaced by phenylalanine, an amino acid with highly similar properties. This mutation has been identified in three brothers diagnosed with medullary thyroid cancer (MTC); three unaffected family members tested negative for this alteration and did not display any clinical or biochemical features of Multiple Endocrine Neoplasia type 2A (MEN2A) (Berndt I et al. J Clin Endocrinol Metab, 1998 Mar;83:770-4). This variant has also been identified in multiple unrelated individuals with a personal history of MTC (Machens A et al. Hum Mutat, 2018 06;39:860-869). Another variant at this position resulting in the same amino acid change (c.2370G>T) has been identified in individuals and families with MTC and/or pheochromocytoma (PCC) and is classified as a moderate risk mutation (Berndt I et al. J. Clin. Endocrinol. Metab. 1998 Mar;83:770-4; Min JW et al. J Korean Surg Soc. 2012 Mar;82:185-9; Bihan H et al. Head Neck. 2012 Apr;34:493-8; Qi XP et al. Thyroid. 2012 Dec;22:1257-65). In addition to the clinical data presented in the literature, this allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is predicted to be deleterious by in silico analysis. 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;25:567-610). Based on the supporting evidence, this variant is expected to be a pathogenic mutation with moderate risk of MEN2; however, its clinical significance for Hirschsprung disease is unclear.
Myriad Genetics, Inc.	RCV000014960	SCV004018494	pathogenic	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28946813, 33827484, 33167350, 12490841, 12409662, 9506724, 25810047].
OMIM	RCV000014960	SCV000035216	pathogenic	Multiple endocrine neoplasia type 2A	1998-03-01	no assertion criteria provided	literature only
OMIM	RCV000014961	SCV000035217	pathogenic	Familial medullary thyroid carcinoma	1998-03-01	no assertion criteria provided	literature only