rs55725216
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001040108.2(MLH3):c.1637G>T(p.Arg546Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,613,594 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R546G) has been classified as Uncertain significance.
Frequency
Consequence
NM_001040108.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH3 | NM_001040108.2 | c.1637G>T | p.Arg546Ile | missense_variant | 2/13 | ENST00000355774.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH3 | ENST00000355774.7 | c.1637G>T | p.Arg546Ile | missense_variant | 2/13 | 5 | NM_001040108.2 | P1 | |
MLH3 | ENST00000380968.6 | c.1637G>T | p.Arg546Ile | missense_variant | 2/12 | 1 | |||
MLH3 | ENST00000556257.5 | c.1637G>T | p.Arg546Ile | missense_variant | 2/7 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000499 AC: 76AN: 152170Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000767 AC: 192AN: 250382Hom.: 1 AF XY: 0.000945 AC XY: 128AN XY: 135422
GnomAD4 exome AF: 0.000521 AC: 761AN: 1461306Hom.: 5 Cov.: 35 AF XY: 0.000644 AC XY: 468AN XY: 726904
GnomAD4 genome AF: 0.000486 AC: 74AN: 152288Hom.: 1 Cov.: 33 AF XY: 0.000618 AC XY: 46AN XY: 74464
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2020 | 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. - |
Colorectal cancer, hereditary nonpolyposis, type 7 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
MLH3-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 18, 2020 | 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