Submissions for variant NM_020975.6(RET):c.2611G>A (p.Val871Ile)

gnomAD frequency: 0.00008  dbSNP: rs145170911

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000034773	SCV000113991	uncertain significance	not provided	2013-10-24	criteria provided, single submitter	clinical testing
Invitae	RCV000123312	SCV000166619	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 871 of the RET protein (p.Val871Ile). This variant is present in population databases (rs145170911, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 31510104). ClinVar contains an entry for this variant (Variation ID: 41842). 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 disruptive. 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.
Counsyl	RCV000409480	SCV000489987	uncertain significance	Multiple endocrine neoplasia, type 2b	2016-09-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000410572	SCV000489988	uncertain significance	Multiple endocrine neoplasia, type 2a	2016-09-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477060	SCV000611516	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a	2022-04-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562304	SCV000664502	benign	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000410572	SCV000838405	uncertain significance	Multiple endocrine neoplasia, type 2a	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763649	SCV000894529	uncertain significance	Congenital central hypoventilation; Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a	2018-10-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000562304	SCV002529985	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-11	criteria provided, single submitter	curation
GeneDx	RCV000034773	SCV002576084	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with medullary thyroid carcinoma and in an individual with breast cancer (Elisei et al., 2019; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 22703879, 26034076, 24336963, 31822803, 14633923, 37375228, 31510104, 35264596)
Myriad Genetics, Inc.	RCV000410572	SCV004018083	uncertain significance	Multiple endocrine neoplasia, type 2a	2023-04-18	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387739	SCV004100064	likely benign	not specified	2023-09-21	criteria provided, single submitter	clinical testing	Variant summary: RET c.2611G>A (p.Val871Ile) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250112 control chromosomes. The observed variant frequency is approximately 2-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 benign. c.2611G>A has been reported in the literature in individuals affected with hereditary medullary thyroid carcinoma, breast cancer, congenital anomalies of the kidney and urinary tract, and atherosclerosis, with no strong evidence for causality (example, Elisei_2019, Guindalini_2022, Hwang_2014, Johnston_2012). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31510104, 35264596, 24429398, 22703879). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=8, Benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034773	SCV000043478	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.