Submissions for variant NM_020975.6(RET):c.1832G>T (p.Cys611Phe)

dbSNP: rs377767397

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021787	SCV001579532	pathogenic	Multiple endocrine neoplasia, type 2	2023-06-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys611 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9230192, 20979234, 27809725, 28099363). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 24899). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 8626834, 11331212, 20979234). 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 cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 611 of the RET protein (p.Cys611Phe).
Ambry Genetics	RCV002408472	SCV002716954	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	The p.C611F pathogenic mutation (also known as c.1832G>T), located in coding exon 10 of the RET gene, results from a G to T substitution at nucleotide position 1832. The cysteine at codon 611 is replaced by phenylalanine, an amino acid with highly dissimilar properties. Multiple mutations at codon 611 have been associated with Hirschsprung Disease (HSCR), Multiple Endocrine Neoplasia Type 2A (MEN2A), and Familial Medullary Thyroid Cancer (FMTC) (Eng C et al. JAMA. 1996 Nov;276:1575-9; Nishikawa M et al. Eur J Hum Genet. 2003 May;11(5):364-8). The p.C611F pathogenic mutation has been reported in numerous families diagnosed with MEN2A (Frank-Raue K et al. J. Clin. Endocrinol. Metab. 1996 May;81:1780-3; Siggelkow H et al. Eur. J. Endocrinol. 2001 May;144:467-73). 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; Wells SA et al. Thyroid. 2015 Jun;25:567-610). This amino acid position is highly conserved in available vertebrate species. 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 unknown.
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV003233027	SCV003930397	pathogenic	Multiple endocrine neoplasia type 2A	2023-05-21	criteria provided, single submitter	clinical testing