chr7-116755424-C-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_000245.4(MET):c.1771C>T(p.Arg591Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,872 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. R591Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000245.4 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.1771C>T | p.Arg591Trp | missense_variant | 6/21 | ENST00000397752.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.1771C>T | p.Arg591Trp | missense_variant | 6/21 | 1 | NM_000245.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 151948Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249354Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135272
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727196
GnomAD4 genome AF: 0.000151 AC: 23AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74312
ClinVar
Submissions by phenotype
Papillary renal cell carcinoma type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 08, 2023 | The MET c.1771C>T (p.Arg591Trp)? missense change has a maximum subpopulation frequency of 0.037% 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 provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 04, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in healthy individuals undergoing whole genome sequencing and in individual(s) with breast cancer (Bodian et al., 2014; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 24728327, 35264596, 33255238) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 07, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Vantari Genetics | Feb 04, 2016 | - - |
MET-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 03, 2023 | The MET c.1771C>T variant is predicted to result in the amino acid substitution p.Arg591Trp. This variant was reported in an individual with breast cancer (Table S3, Guindalini et al. 2022. PubMed ID: 35264596) and in an individual with non-small cell lung cancer (Table S2, Zheng et al. 2020. PubMed ID: 33255238). However, it has also been reported in a cohort healthy individuals (Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.037% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in ClinVar of likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/134654/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
Renal cell carcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at