Submissions for variant NM_020975.6(RET):c.1124T>A (p.Leu375Gln)

gnomAD frequency: 0.00066  dbSNP: rs142338976

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083800	SCV000261223	likely benign	Multiple endocrine neoplasia, type 2	2025-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564599	SCV000674772	likely benign	Hereditary cancer-predisposing syndrome	2020-07-15	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.
Eurofins Ntd Llc (ga)	RCV000591528	SCV000704870	uncertain significance	not provided	2017-02-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001294030	SCV001482795	uncertain significance	Congenital central hypoventilation	2018-11-18	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532950	SCV001748766	likely benign	not specified	2021-06-21	criteria provided, single submitter	clinical testing	Variant summary: RET c.1124T>A (p.Leu375Gln) results in a non-conservative amino acid change located in the Tyrosine-protein kinase receptor Ret, cadherin like domain 3 (IPR040667) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 250980 control chromosomes, predominantly at a frequency of 0.0019 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 51 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. c.1124T>A has been reported in the literature as a VUS in settings of multigene cancer panel testing among individuals affected with a variety of cancers such as high grade glioma, T-cell ALL and in the TGCA cohort (example, Zhang_2018, Yehia_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000591528	SCV001789753	likely benign	not provided	2018-10-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28873162, 24336963)
Genetic Services Laboratory, University of Chicago	RCV001532950	SCV002069502	likely benign	not specified	2018-04-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564599	SCV002529913	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV001083800	SCV005430318	likely benign	Multiple endocrine neoplasia, type 2	2024-08-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001083800	SCV006061783	likely benign	Multiple endocrine neoplasia, type 2	2022-11-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530231	SCV004747312	likely benign	RET-related disorder	2019-05-22	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).