Submissions for variant NM_020975.6(RET):c.1150C>G (p.Pro384Ala)

gnomAD frequency: 0.00006  dbSNP: rs536298339

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197885	SCV000255042	uncertain significance	Multiple endocrine neoplasia, type 2	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 384 of the RET protein (p.Pro384Ala). This variant is present in population databases (rs536298339, gnomAD 0.06%). 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: 216713). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Probably Damaging". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000412082	SCV000489895	uncertain significance	Multiple endocrine neoplasia type 2B	2016-07-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000410243	SCV000489896	uncertain significance	Multiple endocrine neoplasia type 2A	2016-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567892	SCV000674890	benign	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
All of Us Research Program, National Institutes of Health	RCV000197885	SCV005430321	uncertain significance	Multiple endocrine neoplasia, type 2	2024-03-25	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 384 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. This variant has been identified in 12/282426 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.
GeneDx	RCV005055722	SCV005690141	uncertain significance	not provided	2024-08-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923)