ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2290G>A (p.Ala764Thr)

gnomAD frequency: 0.00004  dbSNP: rs748799148
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000576114 SCV000674840 benign Hereditary cancer-predisposing syndrome 2023-01-26 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000654575 SCV000776469 uncertain significance Multiple endocrine neoplasia, type 2 2024-10-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 764 of the RET protein (p.Ala764Thr). This variant is present in population databases (rs748799148, gnomAD 0.007%). 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: 486317). 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.
Fulgent Genetics, Fulgent Genetics RCV002476250 SCV002783657 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2022-01-12 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000654575 SCV004828179 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 764 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 9/251010 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 RCV004592777 SCV005077993 uncertain significance not provided 2024-03-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (PMID: 36200007); This variant is associated with the following publications: (PMID: 30972172, 14633923, 36200007)

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