rs63750449
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 5P and 20B. PM1PM5PP3BP4_StrongBP6_Very_StrongBS1BS2
The NM_000249.4(MLH1):c.1853A>C(p.Lys618Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,614,148 control chromosomes in the GnomAD database, including 23 homozygotes. 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. K618A) has been classified as Benign.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1853A>C | p.Lys618Thr | missense_variant | 16/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1853A>C | p.Lys618Thr | missense_variant | 16/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00391 AC: 595AN: 152188Hom.: 2 Cov.: 31
GnomAD3 exomes AF: 0.00347 AC: 873AN: 251414Hom.: 4 AF XY: 0.00342 AC XY: 465AN XY: 135870
GnomAD4 exome AF: 0.00487 AC: 7113AN: 1461842Hom.: 21 Cov.: 31 AF XY: 0.00470 AC XY: 3417AN XY: 727230
GnomAD4 genome ? AF: 0.00390 AC: 594AN: 152306Hom.: 2 Cov.: 31 AF XY: 0.00411 AC XY: 306AN XY: 74472
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:6
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 12, 2019 | - - |
Uncertain significance, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 10, 2020 | The p.Lys618Thr variant in MLH1 is classified as benign because it has been identified in 0.57% (735/129116, 2 homozygotes) chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is a common haplotype with c.1852A>G. ACMG/AMP Criteria applied: BA1. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, 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 | Eurofins Ntd Llc (ga) | Sep 24, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 03, 2017 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 01, 2022 | - - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 10, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 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. - |
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Nov 22, 2022 | - - |
not provided Uncertain:1Benign:1Other:1
not provided, no classification provided | literature only | Harris Lab, University of Minnesota | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | MLH1: PP3, BS2 - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 10, 2019 | 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
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 | Jun 22, 2023 | - - |
Lynch syndrome 1 Benign:1
Likely benign, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 21, 2022 | - - |
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 - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at