7-116699749-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_000245.4(MET):c.665C>T(p.Thr222Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,614,002 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. T222R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000245.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.665C>T | p.Thr222Met | missense_variant | Exon 2 of 21 | ENST00000397752.8 | NP_000236.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000178 AC: 27AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000683 AC: 17AN: 249042Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135096
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461786Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27AN XY: 727190
GnomAD4 genome AF: 0.000177 AC: 27AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74426
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
- -
MET-related disorder Uncertain:1
The MET c.665C>T variant is predicted to result in the amino acid substitution p.Thr222Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.045% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
Observed in an individual with an advanced cancer, not otherwise specified (PMID: 28873162); 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: 37200850, 28873162) -
Papillary renal cell carcinoma type 1 Uncertain:1
The MET c.665C>T (p.Thr222Met) missense change has a maximum subpopulation frequency of 0.05% 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, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with hereditary papillary renal cell carcinoma. 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 Benign:1
Variant summary: MET c.665C>T (p.Thr222Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 249042 control chromosomes. The observed variant frequency is approximately 45.51 fold of the estimated maximal expected allele frequency for a pathogenic variant in MET causing Papillary Renal Cell Carcinoma phenotype (1.5e-06). To our knowledge, no occurrence of c.665C>T in individuals affected with MET-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37200850, 32758285, 36430388, 34663923). ClinVar contains an entry for this variant (Variation ID: 216514). Based on the evidence outlined above, the variant was classified as likely benign. -
Renal cell carcinoma Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at