Submissions for variant NM_020975.6(RET):c.1921G>A (p.Ala641Thr)

gnomAD frequency: 0.00001  dbSNP: rs377767411

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229577	SCV000290540	uncertain significance	Multiple endocrine neoplasia, type 2	2024-12-12	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 641 of the RET protein (p.Ala641Thr). This variant is present in population databases (rs377767411, gnomAD 0.01%). 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: 241342). 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.
Counsyl	RCV000662388	SCV000784793	uncertain significance	Multiple endocrine neoplasia type 2A	2016-12-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001292757	SCV001481399	uncertain significance	Familial medullary thyroid carcinoma	2020-02-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002411060	SCV002717418	likely benign	Hereditary cancer-predisposing syndrome	2021-11-08	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.
Fulgent Genetics, Fulgent Genetics	RCV002487084	SCV002783504	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV002508206	SCV002818053	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with congenital anomalies of the kidney and urinary tract (Ahn et al., 2020); Published functional studies demonstrate no damaging effect: RET protein phosphorylation and cell viability similar to wildtype (Guan et al., 2020); This variant is associated with the following publications: (PMID: 29338689, 17934909, 25900796, 32164334, 32293499, 14633923, 29192238)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000662388	SCV003843053	uncertain significance	Multiple endocrine neoplasia type 2A	2022-01-06	criteria provided, single submitter	clinical testing	The RET c.1921G>A (p.Ala641Thr) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, however functional studies performed on cell lines suggest that this variant does not activate RET kinase (PMID: 32293499). This variant has been reported in an individual with bilateral renal dysplasia, horseshoe kidney, and left vesicoureteral reflux (PMID: 32164334). To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type IIA or type IIB. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV000662388	SCV004018035	likely benign	Multiple endocrine neoplasia type 2A	2024-08-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Baylor Genetics	RCV003463677	SCV004208673	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-09-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000229577	SCV004824349	uncertain significance	Multiple endocrine neoplasia, type 2	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 641 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). Functional study reported that this variant does not affect the oncogenic potential of RET in a mouse and an ex vivo cell culture model and does not activate RET kinase activity in vitro (PMID: 32293499). This variant has been reported in one individual each affected with medullary thyroid cancer without pheochromocytoma or hyperparathyroidism (doi: 10.4183/aeb.2015.189) or ovarian cancer (PMID: 32293499), respectively. This variant has been identified in 10/248620 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.