chr10-43114491-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4BP6
The NM_020975.6(RET):c.1891G>A(p.Asp631Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,606,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D631Y) has been classified as Pathogenic.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1891G>A | p.Asp631Asn | missense_variant | Exon 11 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151932Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000405 AC: 10AN: 246932Hom.: 0 AF XY: 0.0000448 AC XY: 6AN XY: 133928
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1454852Hom.: 0 Cov.: 32 AF XY: 0.00000691 AC XY: 5AN XY: 724054
GnomAD4 genome AF: 0.0000395 AC: 6AN: 151932Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74180
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia type 2A Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 09, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 15, 2024 | The RET c.1891G>A (p.Asp631Asn) missense change has a maximum subpopulation frequency of 0.04% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant has been reported in the literature in an individual with medullary thyroid cancer (PMID: 30927507). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 25, 2019 | - - |
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 27, 2022 | - - |
Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 22, 2023 | - - |
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 27, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 631 of the RET protein (p.Asp631Asn). This variant is present in population databases (rs377767406, gnomAD 0.03%). This missense change has been observed in individual(s) with RET-related conditions (PMID: 30927507, 35534704). ClinVar contains an entry for this variant (Variation ID: 24913). 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. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 10049754). This variant disrupts the p.Asp631 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10049754, 16839264, 22274720). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate absent transforming activity and no independent dimerization (PMID: 10049754); This variant is associated with the following publications: (PMID: 23264394, 26639839, 21479187, 25810047, 14633923, 10049754, 30927507, 35534704) - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at