Submissions for variant NM_020975.6(RET):c.2710T>G (p.Ser904Ala)

dbSNP: rs1588877711

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824078	SCV000964960	uncertain significance	Multiple endocrine neoplasia, type 2	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 904 of the RET protein (p.Ser904Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 665731). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002427074	SCV002741401	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.S904A variant (also known as c.2710T>G), located in coding exon 15 of the RET gene, results from a T to G substitution at nucleotide position 2710. The serine at codon 904 is replaced by alanine, an amino acid with similar properties. Other alterations at codon 904 have been detected in MEN 2B and medullary thyroid cancer families; however the pathogenicity of these alterations remains unclear (Elisei R et al, J. Clin. Endocrinol. Metab. 2007 Dec; 92(12):4725-9. Menko FH et al, J. Clin. Endocrinol. Metab. 2002 Jan; 87(1):393-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002478933	SCV002782298	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-01-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000824078	SCV004815283	uncertain significance	Multiple endocrine neoplasia, type 2	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 904 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.2711C>T (p.Ser904Phe), is considered to be pathogenic (ClinVar Variation ID: 36304), suggesting that Ser at this position is important for protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Daryl Scott Lab, Baylor College of Medicine	RCV005225160	SCV005871357	uncertain significance	RET-related disorder	2024-01-01	criteria provided, single submitter	clinical testing	PM2, PP3