Submissions for variant NM_020975.6(RET):c.961G>A (p.Gly321Arg) (rs377767388)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER_CC_NCGL; University of Washington Medical Center	RCV000148776	SCV000190513	uncertain significance	Medullary thyroid carcinoma	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Invitae	RCV000231209	SCV000290569	uncertain significance	Multiple endocrine neoplasia, type 2	2018-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 321 of the RET protein (p.Gly321Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs377767388, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a single family affected with medullary thyroid carcinoma and/or C-cell hyperplasia. However, the variant did not segregate with disease in this family (PMID: 16419493). ClinVar contains an entry for this variant (Variation ID: 24881). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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	RCV000567555	SCV000674744	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-19	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
PreventionGenetics,PreventionGenetics	RCV000679758	SCV000807066	uncertain significance	not provided	2018-01-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000709104	SCV000838373	uncertain significance	Multiple endocrine neoplasia, type 2a	2018-07-02	criteria provided, single submitter	clinical testing
Research and Development, ARUP Laboratories	RCV000021762	SCV000042428	uncertain significance	not specified	2018-05-04	no assertion criteria provided	literature only	Single Czech family report, 4 have the variant genotype: 1 metastatic MTC (61 yr), 1 bi-lateral C-cell hyperplasia (42 yr).

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