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

gnomAD frequency: 0.00009  dbSNP: rs377767388

Total submissions: 11

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
Labcorp Genetics (formerly Invitae), Labcorp	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: seen in unaffected individuals, 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	RCV004528128	SCV000807066	uncertain significance	RET-related disorder	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
CeGaT Center for Human Genetics Tuebingen	RCV000679758	SCV004699800	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	RET: PM2, BP4