10-43112903-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1
The NM_020975.6(RET):c.1699G>A(p.Asp567Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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RET | NM_020975.6 | c.1699G>A | p.Asp567Asn | missense_variant | Exon 9 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000171 AC: 43AN: 251392Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135896
GnomAD4 exome AF: 0.000133 AC: 195AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 88AN XY: 727218
GnomAD4 genome AF: 0.000131 AC: 20AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21490379, 27834349, 27884173, 14633923) -
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RET: BS2 -
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Hereditary cancer-predisposing syndrome Benign:3
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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. -
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not specified Uncertain:2
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Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Only reported in proband with renal agenesis; ExAC: 0.1% (9/11538) Latino; ClinVar: 2 VUS -
Multiple endocrine neoplasia, type 2 Uncertain:1Benign:1
This missense variant replaces aspartic acid with asparagine at codon 567 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). A functional study has reported that this variant causes ectopic RET dimerization, activation of kinase activity and tumor formation in murine allograft growth assay (PMID: 36166639). This variant has been reported in a fetus affected with renal agenesis and an unaffected parent and in a Latina individual affected with adrenal medullary hyperplasia (PMID: 21490379, 32732076). This variant has been identified in 46/282764 chromosomes in the general population, including 22/35434 chromosomes in the Latino 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. -
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Renal hypodysplasia/aplasia 1 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Multiple endocrine neoplasia type 2A Uncertain:1
The RET c.1699G>A (p.Asp567Asn) missense change has a maximum subpopulation frequency of 0.062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant occurs in the extracellular calmodulin-like motif (CaLM) in the cysteine rich domain, recently described as the location of a novel 3D cluster of oncogenic mutations in RET (PMID: 36166639). The in silico tool REVEL predicts a deleterious effect on protein function, and a molecular dynamics assay of mutations in CaLM and showed that this variant affects the conformational integrity of the RET-Ca2+ ion complex, underlying oncogenic properties which are increased in the presence of ligands/co-receptors that facilitate dimerization (PMID: 36166639). An in-vivo study showed that this variant is potentially druggable after existing RET-TKIs drugs, selpercatinib and pralsetinib, were shown to suppress the growth of NIH3T3 cells expressing p.Asp567Asn similar to their effect on NIH3T3 cells expressing known pathogenic mutations (PMID: 36166639). 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. -
Familial medullary thyroid carcinoma Uncertain:1
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Pheochromocytoma Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Hirschsprung disease, susceptibility to, 1 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Multiple endocrine neoplasia Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
RET-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at