chr10-43120084-G-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_020975.6(RET):c.2611G>A(p.Val871Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,613,782 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).
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.2611G>A | p.Val871Ile | missense_variant | Exon 15 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000840 AC: 21AN: 250112Hom.: 0 AF XY: 0.0000738 AC XY: 10AN XY: 135490
GnomAD4 exome AF: 0.000105 AC: 153AN: 1461456Hom.: 0 Cov.: 34 AF XY: 0.000109 AC XY: 79AN XY: 727018
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152326Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:4
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In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with medullary thyroid carcinoma and in an individual with breast cancer (Elisei et al., 2019; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 22703879, 26034076, 24336963, 31822803, 14633923, 37375228, 31510104, 35264596) -
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Multiple endocrine neoplasia type 2A Uncertain:1Benign:2
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. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
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Multiple endocrine neoplasia type 2B Uncertain:1
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Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
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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
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Multiple endocrine neoplasia, type 2 Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 871 of the RET protein (p.Val871Ile). This variant is present in population databases (rs145170911, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 31510104). ClinVar contains an entry for this variant (Variation ID: 41842). 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 specified Benign:1
Variant summary: RET c.2611G>A (p.Val871Ile) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250112 control chromosomes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is benign. c.2611G>A has been reported in the literature in individuals affected with hereditary medullary thyroid carcinoma, breast cancer, congenital anomalies of the kidney and urinary tract, and atherosclerosis, with no strong evidence for causality (example, Elisei_2019, Guindalini_2022, Hwang_2014, Johnston_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31510104, 35264596, 24429398, 22703879). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=8, Benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at