Submissions for variant NM_020975.6(RET):c.1591T>C (p.Cys531Arg)

dbSNP: rs377767390

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021766	SCV000948990	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 531 of the RET protein (p.Cys531Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of multiple endocrine neoplasia type 2 (PMID: 20103606, 27838608, 28946813, 30877234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24885). An algorithm developed specifically for the RET gene suggests that this missense change is likely to be deleterious (PMID: 21479187). Experimental studies have shown that this missense change affects RET function (PMID: 20103606). 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	RCV002399332	SCV002708985	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	The p.C531R variant (also known as c.1591T>C), located in coding exon 8 of the RET gene, results from a T to C substitution at nucleotide position 1591. The cysteine at codon 531 is replaced by arginine, an amino acid with highly dissimilar properties. This variant was detected in an individual with medullary thyroid cancer (MTC) diagnosed at age 53, and the p.C531R variant was found to generate RET and ERK phosphorylation levels and to have a transforming activity higher than that of a wild-type variant, but lower than that of a known pathogenic variant (Muzza M et al. Eur J Endocrinol, 2010 Apr;162:771-7). This variant was also detected in two affected sisters. One of the sisters was diagnosed with a right pheochromocytoma at the age of 44 and at age 53 she developed an invasive left pheochromocytoma with no other endocrine neoplasia. The other sister was diagnosed with a left pheochromocytoma at age 50 and at age 64 she had a right pheochromocytoma and MTC.(Martins AF et al. Hormones (Athens), 2016 Jul;15:435-440). This variant has also been reported in a cohort of 5109 index cases of endocrine neoplasia from France (Lebeault M et al. Thyroid, 2017 12;27:1511-1522). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004700263	SCV005201972	likely pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a moderate increase in phosphorylation and transforming activity (Muzza et al., 2010); 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; This variant is associated with the following publications: (PMID: 25725622, 20103606, 30877234, 21479187, 28946813, 27838608, 14633923)