Submissions for variant NM_020975.6(RET):c.1891G>A (p.Asp631Asn) (rs377767406)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519407	SCV000618423	uncertain significance	not provided	2017-07-31	criteria provided, single submitter	clinical testing	The D631N variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in medullary thyroid cancer (Agrawal et al., 2013). Functional studies show D631N results in absent transforming activity and no independent dimerization, as compared to a known pathogenic variant. This suggests that D631N is not pathogenic (Asai et al., 1999). This variant was observed at an allele frequency of 0.05% (4/8626) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek et al., 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. This substitution occurs at a position that is not conserved and is located in the intracellular domain and Cystein-rich domain (Garcia-Barcelo et al., 2004). Based on currently available evidence, we consider D631N to be a variant of uncertain significance.
Ambry Genetics	RCV000564566	SCV000674829	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-01	criteria provided, single submitter	clinical testing	The p.D631N variant (also known as c.1891G>A), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide position 1891. The aspartic acid at codon 631 is replaced by asparagine, an amino acid with highly similar properties. According to the American Thyroid Association, a different alteration at this codon (p.D631Y) is considered a mutation that confers moderate risk for medullary thyroid cancer and increased risk for pheochromocytoma; however, p.D631N was not described (Wells SA, et al. Thyroid 2015 Jun; 25(6):567-610). In one functional study, this alteration was shown to display very low/undetectable transforming activity, in contrast to the p.D631Y mutant, prompting authors to suggest that only specific alterations at this residue are associated with pathogenesis (Asai N, et al. Biochem. Biophys. Res. Commun. 1999 Feb; 255(3):587-90). Based on protein sequence alignment, this amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000696792	SCV000825371	uncertain significance	Multiple endocrine neoplasia, type 2	2020-06-06	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 631 of the RET protein (p.Asp631Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs377767406, ExAC 0.05%). This variant has been observed in individual(s) with medullary thyroid carcinoma (PMID: 30927507). ClinVar contains an entry for this variant (Variation ID: 24913). Experimental studies have shown that this missense change does not result in RET protein activation (PMID: 10049754). A different variant affecting this nucleotide (p.Asp631Tyr) has been determined to be pathogenic (PMID: 16839264, 10049754, 22274720). This suggests that this nucleotide is important for normal protein function, and that other variants at this position may also be pathogenic. 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.
Fulgent Genetics,Fulgent Genetics	RCV000764898	SCV000896058	uncertain significance	Congenital central hypoventilation; Hirschsprung disease 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a	2018-10-31	criteria provided, single submitter	clinical testing