rs63750702
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_ModerateBP6_Very_Strong
The NM_000249.4(MLH1):c.2066A>G(p.Gln689Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000306 in 1,614,048 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q689H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.2066A>G | p.Gln689Arg | missense_variant | 18/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.2066A>G | p.Gln689Arg | missense_variant | 18/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000263 AC: 66AN: 251170Hom.: 0 AF XY: 0.000309 AC XY: 42AN XY: 135732
GnomAD4 exome AF: 0.000317 AC: 464AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.000316 AC XY: 230AN XY: 727220
GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74380
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:6
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 22, 2021 | Variant summary: MLH1 c.2066A>G (p.Gln689Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 253582 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (0.00028 vs 0.00071), allowing no conclusion about variant significance. c.2066A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. c.2066A>G has been reported in the literature in individuals affected with microsatellite stable colorectal, endometrioid, rectal and breast cancers but also associated with normal IHC and also found in controls (example, Hampel_2006, Barnetson_2008, Hinrichsen_2015, Pinto_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in no or mild functional impairment in mismatch repair (MMR) activity associated with this variant and no effect on splicing (Hardt_2011, Hinrichsen_2015, Takahashi_2007, Tournier_2008). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=2; likely benign, n=4; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging consensus among peers supporting a neutral outcome as outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in multiple papers in HGMD, with the comments suggesting the variant is benign and possible protective. Classified in ClinVar as Benign by Expert panel (3 stars) and 3 other submitters (Invitae, Ambry, GeneDx). MaxMAF = .05% (high for disease prevalence) - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 25, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 20, 2021 | - - |
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 01, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 11, 2014 | 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 08, 2020 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | MLH1: BP1, BS3:Moderate, BS1 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2018 | This variant is associated with the following publications: (PMID: 27553368, 22736432, 21404117, 17510385, 25477341, 25637381, 22949387, 18033691, 11726306, 18561205, 18383312, 24362816, 22290698, 16885385, 30998989) - |
Colorectal cancer, non-polyposis Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 25, 2023 | - - |
Lynch syndrome Benign:1
Benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability <0.001 - |
MLH1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 03, 2019 | 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). - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at