Submissions for variant NM_020975.6(RET):c.2080C>T (p.Arg694Trp)

gnomAD frequency: 0.00001  dbSNP: rs193922700

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000770758	SCV000053075	uncertain significance	not specified	2019-02-20	criteria provided, single submitter	clinical testing	Variant summary: RET c.2080C>T (p.Arg694Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 275790 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2080C>T has been reported in the literature in an individual affected with breast cancer (Sun_2017). This report does 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000030406	SCV000786028	uncertain significance	Multiple endocrine neoplasia type 2A	2018-02-06	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000708755	SCV000822194	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698016	SCV000826654	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 694 of the RET protein (p.Arg694Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with indications for hereditary breast and ovarian cancer syndrome or with meduloblastoma (PMID: 28724667, 31159747, 34308104). ClinVar contains an entry for this variant (Variation ID: 36727). 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.
Ambry Genetics	RCV000708755	SCV002729861	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.R694W variant (also known as c.2080C>T), located in coding exon 11 of the RET gene, results from a C to T substitution at nucleotide position 2080. The arginine at codon 694 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000030406	SCV004018484	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.
PreventionGenetics, part of Exact Sciences	RCV004528140	SCV004112123	uncertain significance	RET-related disorder	2023-09-18	criteria provided, single submitter	clinical testing	The RET c.2080C>T variant is predicted to result in the amino acid substitution p.Arg694Trp. This variant was reported in individuals with breast cancer, medulloblastoma, or a personal or family history of cancer (Table S3, Sun et al. 2017. PubMed ID: 28724667; described as chr10:43610128C>T Table S2, Kim et al. 2021. PubMed ID: 34308104; Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is listed as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/36727/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.