Submissions for variant NM_020975.6(RET):c.262A>G (p.Ile88Val)

gnomAD frequency: 0.00056  dbSNP: rs141679950

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168298	SCV000218978	likely benign	Multiple endocrine neoplasia, type 2	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000412432	SCV000489789	uncertain significance	Multiple endocrine neoplasia, type 2b	2016-03-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000410050	SCV000489790	uncertain significance	Multiple endocrine neoplasia, type 2a	2016-03-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563081	SCV000674769	likely benign	Hereditary cancer-predisposing syndrome	2018-10-31	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.
Mendelics	RCV000410050	SCV000838366	likely benign	Multiple endocrine neoplasia, type 2a	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781813	SCV000920149	benign	not specified	2018-02-16	criteria provided, single submitter	clinical testing	Variant summary: RET c.262A>G (p.Ile88Val) results in a conservative amino acid change located in the outside of any known functional domain or repeat of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 51.3 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 origin. To our knowledge, no occurrence of c.262A>G in individuals affected with Multiple Endocrine Neoplasia Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001582661	SCV001820046	likely benign	not provided	2021-04-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000563081	SCV002529987	likely benign	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003937519	SCV004755087	likely benign	RET-related condition	2019-11-18	criteria provided, single submitter	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).