Submissions for variant NM_020975.6(RET):c.2166G>T (p.Lys722Asn)

gnomAD frequency: 0.00001  dbSNP: rs527726480

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123307	SCV000166614	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 722 of the RET protein (p.Lys722Asn). This variant is present in population databases (rs527726480, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 136108). 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	RCV000562548	SCV000674863	likely benign	Hereditary cancer-predisposing syndrome	2021-10-08	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.
Mendelics	RCV003492551	SCV000838397	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483239	SCV002785085	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV003159099	SCV003853164	uncertain significance	not provided	2022-09-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 14633923)
Baylor Genetics	RCV003467095	SCV004208677	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-09-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123307	SCV004838660	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 722 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 hereditary cancer in the literature. This variant has been identified in 8/251484 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.