chr10-43120114-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_020975.6(RET):āc.2641C>Gā(p.Leu881Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L881L) has been classified as Likely benign.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.2641C>G | p.Leu881Val | missense_variant | 15/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.2641C>G | p.Leu881Val | missense_variant | 15/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250510Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135636
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461646Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3AN XY: 727116
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia type 2A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2016 | - - |
Multiple endocrine neoplasia type 2B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2016 | - - |
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 881 of the RET protein (p.Leu881Val). This variant is present in population databases (rs377767427, gnomAD 0.003%). This missense change has been observed in individual(s) with medullary thyroid carcinoma, C-cell hyperplasia, and cancer (PMID: 20013610). ClinVar contains an entry for this variant (Variation ID: 24957). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 08, 2019 | Observed in an individual with medullary thyroid microcarcinoma, a relative with C-cell hyperplasia, and two unaffected relatives (Frank-Raue et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21479187, 1479187, 20013610) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 29, 2023 | The p.L881V variant (also known as c.2641C>G), located in coding exon 15 of the RET gene, results from a C to G substitution at nucleotide position 2641. The leucine at codon 881 is replaced by valine, an amino acid with highly similar properties. This alteration was previously identified in an individual with medullary thyroid cancer, as well as both asymptomatic and symptomatic family members, prompting authors to suggest that the alteration is a low risk mutation associated with late onset and incomplete penetrance (Frank-Raue K, et al. Exp. Clin. Endocrinol. Diabetes. 2010 Aug;118:550-3). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at