Submissions for variant NM_020975.6(RET):c.406G>A (p.Glu136Lys)

gnomAD frequency: 0.00002  dbSNP: rs79014735

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197380	SCV000255056	uncertain significance	Multiple endocrine neoplasia, type 2	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 136 of the RET protein (p.Glu136Lys). This variant is present in population databases (rs79014735, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216727). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV000571944	SCV000674779	likely benign	Hereditary cancer-predisposing syndrome	2023-07-12	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.
Counsyl	RCV000662413	SCV000784845	uncertain significance	Multiple endocrine neoplasia type 2A	2017-01-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679750	SCV002774853	uncertain significance	not provided	2024-05-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002503785	SCV002816655	likely benign	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2024-04-25	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153474	SCV003843443	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000679750	SCV003924742	uncertain significance	not provided	2023-03-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with breast cancer, as well as in unaffected controls from a melanoma study (Pritchard et al., 2018; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 14633923, 29684080, BhatiS2016[article], 29641532)
Baylor Genetics	RCV003462339	SCV004206706	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-06-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000197380	SCV004818834	uncertain significance	Multiple endocrine neoplasia, type 2	2024-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 136 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 RET-related disorders in the literature, but was identified in a healthy control individual (PMID: 29641532). This variant has been identified in 22/251406 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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678743	SCV000804915	uncertain significance	not specified	2011-03-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739588	SCV000807054	uncertain significance	RET-related disorder	2024-08-11	no assertion criteria provided	clinical testing	The RET c.406G>A variant is predicted to result in the amino acid substitution p.Glu136Lys. This variant has been reported in a breast cancer specimen from the The Cancer Genome Atlas (TGCA; Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variants has been reported in a control individual from a cutaneous melanoma cohort study (Supplement, Pritchard et al. 2018. PubMed ID: 29641532). This variant is reported in 0.032% of alleles in individuals of Latino descent in gnomAD. It is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/216727/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.