rs63750365
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_ModerateBP6_Very_Strong
The NM_000249.4(MLH1):c.1321G>A(p.Ala441Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,613,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A441V) 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.1321G>A | p.Ala441Thr | missense_variant | 12/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1321G>A | p.Ala441Thr | missense_variant | 12/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000309 AC: 47AN: 152100Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000338 AC: 85AN: 251274Hom.: 0 AF XY: 0.000280 AC XY: 38AN XY: 135808
GnomAD4 exome AF: 0.000343 AC: 502AN: 1461892Hom.: 1 Cov.: 34 AF XY: 0.000318 AC XY: 231AN XY: 727248
GnomAD4 genome ? AF: 0.000309 AC: 47AN: 152100Hom.: 0 Cov.: 31 AF XY: 0.000323 AC XY: 24AN XY: 74300
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 10, 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: Two mammals and one non-mammal have a Thr at this position. It has a max MAF of 0.09% in gnomAD. It is reported in 7 papers in HGMD, classified as DM, most comments suggest VUS. It is classified in ClinVar with 3 stars as Benign by InSiGHT (expert panel) and Pathway genomics, and likely benign by GeneDx and Invitae, and as VUS by Mayo and CSER_CC_NCGL. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 14, 2021 | Variant summary: MLH1 c.1321G>A (p.Ala441Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 251274 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00034 vs 0.00071), allowing no conclusion about variant significance. c.1321G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (example Borg_2000, Cunningham_2001, Mangold_2005, Kurzawski_2006, South_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature and observed in our laboratory (Borg_2000, BRCA1 3166insTGAGA; our laboratory, MSH6 c.999delC, p.Lys334fs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on mismatch repair activity (MMR). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus leaning towards benign/likely benign (n=11). Based on the overwhelming evidence supporting a non-actionable as outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 26, 2021 | - - |
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Feb 28, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 16, 2023 | This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 29, 2018 | 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2020 | This variant is associated with the following publications: (PMID: 16042583, 16438707, 20223024, 21056691, 25637381, 11524701, 19117025, 17510385, 10709098, 22949379, 11376800, 23741719, 15849733, 9326924, 24055113, 27153395, 26659639, 28526081, 21404117, 18383312, 29785566, 17192056, 32547938) - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 03, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 05, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | MLH1: BP4, BS3:Supporting - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 11, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:5
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Aug 30, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 15, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2019 | 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 | curation | Sema4, Sema4 | Mar 04, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Nov 22, 2022 | - - |
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 14, 2023 | - - |
Lynch syndrome 1 Benign:1
Benign, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
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 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at