ClinVar Miner

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

gnomAD frequency: 0.00009  dbSNP: rs377767388
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington 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 2022-10-23 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 321 of the RET protein (p.Gly321Arg). This variant is present in population databases (rs377767388, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of medullary thyroid carcinoma (PMID: 16419493, 27014708). 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, which suggests that this missense change does not adversely affect protein function. 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 likely benign Hereditary cancer-predisposing syndrome 2020-04-15 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Preventiongenetics, part of Exact Sciences RCV003389671 SCV000807066 uncertain significance RET-related condition 2023-10-08 criteria provided, single submitter clinical testing The RET c.961G>A variant is predicted to result in the amino acid substitution p.Gly321Arg. This variant has been reported as potentially causative for familial medullary thyroid carcinoma, and co-segregated with medullary thyroid carcinoma in two patients, but was also identified in two family members without disease at time of publication (Dvorakova et al. 2005. PubMed ID: 16419493). This variant has also been reported in individuals with breast cancer (Table S3, Guindalini et al. 2022. PubMed ID: 35264596), a patient with PTEN-negative Cowden syndrome (Table S9, Yehia et al. 2018. PubMed ID: 29684080), and an individual with advanced cancer (Supplement 2, eTable, Mandelker et al. 2017. PubMed ID: 28873162). Using online prediction tools, other studies have reported this variant as benign (Crockett et al. 2011. PubMed ID: 21479187) and a variant of uncertain significance (Table S1, Amendola et al. 2015. PubMed ID: 25637381; Table S1, Dorschner et al. 2013. PubMed ID: 24055113). Functional studies found this variant has no evidence it is an activating variant (Kovac et al. 2020. PubMed ID: 32179705). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43601917-G-A) and has conflicting interpretations of pathogenicity of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/24881/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mendelics RCV000709104 SCV000838373 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000679758 SCV002011439 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001818171 SCV002069391 uncertain significance not specified 2020-12-21 criteria provided, single submitter clinical testing DNA sequence analysis of the RET gene demonstrated a sequence change, c.961G>A, in exon 5 that results in an amino acid change, p.Gly321Arg. This sequence change has been described in the gnomAD database with a frequency of 0.012% in the European sub-population (dbSNP rs377767388). The p.Gly321Arg change has been reported in a family with medullary thyroid cancer and/or C cell hyperplasia; however, the sequence change did not segregate with disease in the family (PMID: 16419493). The p.Gly321Arg change affects a poorly conserved amino acid residue located in a domain of the RET protein that is known to be functional. The p.Gly321Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly321Arg change remains unknown at this time.
Sema4, Sema4 RCV000567555 SCV002527937 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-09 criteria provided, single submitter curation
Baylor Genetics RCV003460487 SCV004208632 uncertain significance Hirschsprung disease, susceptibility to, 1 2023-10-30 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001818171 SCV004243365 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.