Submissions for variant NM_020975.6(RET):c.2601G>T (p.Glu867Asp)

gnomAD frequency: 0.00011  dbSNP: rs141459368

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197994	SCV000255048	likely benign	Multiple endocrine neoplasia, type 2	2025-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001016073	SCV001176985	likely benign	Hereditary cancer-predisposing syndrome	2020-07-07	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.
Sema4, Sema4	RCV001016073	SCV002529984	likely benign	Hereditary cancer-predisposing syndrome	2021-04-01	criteria provided, single submitter	curation
GeneDx	RCV003225040	SCV003921732	uncertain significance	not provided	2022-10-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923, 26934580)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987446	SCV004803421	likely benign	not specified	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: RET c.2601G>T (p.Glu867Asp) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249872 control chromosomes, predominantly at a frequency of 0.00086 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 23 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2601G>T in individuals affected with Multiple Endocrine Neoplasia Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 216719). Based on the evidence outlined above, the variant was classified as likely benign.
Myriad Genetics, Inc.	RCV004791321	SCV005403638	likely benign	Multiple endocrine neoplasia type 2A	2024-08-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
PreventionGenetics, part of Exact Sciences	RCV004530196	SCV004738205	likely benign	RET-related disorder	2022-04-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).