Submissions for variant NM_020975.6(RET):c.2129A>G (p.Lys710Arg)

gnomAD frequency: 0.00001  dbSNP: rs774983492

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneKor MSA	RCV000708756	SCV000822195	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000703840	SCV000832762	uncertain significance	Multiple endocrine neoplasia, type 2	2022-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 710 of the RET protein (p.Lys710Arg). This variant is present in population databases (rs774983492, gnomAD 0.002%). 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: 580338). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics	RCV000709118	SCV000838396	uncertain significance	Multiple endocrine neoplasia, type 2a	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708756	SCV001175269	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-03	criteria provided, single submitter	clinical testing	The p.K710R variant (also known as c.2129A>G), located in coding exon 11 of the RET gene, results from an A to G substitution at nucleotide position 2129. The lysine at codon 710 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this/these patient(s) was diagnosed with medulloblastoma (Zhang J et al. N Engl J Med. 2015 Dec;373:2336-2346). This alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer1 2019 Jun;19:535). This amino acid position is highly 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.
Illumina Laboratory Services, Illumina	RCV001104665	SCV001261543	uncertain significance	Multiple endocrine neoplasia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104666	SCV001261544	uncertain significance	Pheochromocytoma	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104667	SCV001261545	uncertain significance	Renal hypodysplasia/aplasia 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001104668	SCV001261546	uncertain significance	Hirschsprung disease, susceptibility to, 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Fulgent Genetics, Fulgent Genetics	RCV002499266	SCV002814882	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a	2022-05-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001104668	SCV004208639	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-10-24	criteria provided, single submitter	clinical testing