Submissions for variant NM_020975.6(RET):c.539G>A (p.Arg180Gln)

gnomAD frequency: 0.00003  dbSNP: rs370736139

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000148786	SCV000190524	uncertain significance	Aganglionic megacolon	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	RCV000197537	SCV000253568	likely benign	Multiple endocrine neoplasia, type 2	2024-01-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000412078	SCV000489769	uncertain significance	Multiple endocrine neoplasia type 2B	2015-12-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000410075	SCV000489770	uncertain significance	Multiple endocrine neoplasia type 2A	2015-12-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000410075	SCV001138020	benign	Multiple endocrine neoplasia type 2A	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024031	SCV001185984	likely benign	Hereditary cancer-predisposing syndrome	2020-10-22	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.
Baylor Genetics	RCV001294034	SCV001482799	uncertain significance	Familial medullary thyroid carcinoma	2020-04-10	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736605	SCV004562535	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	The RET c.539G>A; p.Arg180Gln variant (rs370736139) is reported in the literature in an individual affected with Hirschsprung disease (Hofstra 2000). This variant is also reported in ClinVar (Variation ID: 161360). This variant is found in the Latino population with an allele frequency of 0.08% (27/35,432 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.223). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Hofstra RM et al. RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Hum Mutat. 2000;15(5):418-29. PMID: 10790203.
All of Us Research Program, National Institutes of Health	RCV000197537	SCV004838627	uncertain significance	Multiple endocrine neoplasia, type 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 180 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MEN2 or medullary thyroid carcinoma. This variant has been reported in an individual affected with Hirschsprung disease (PMID: 10790203). This variant has been identified in 37/282728 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.