chr3-37001050-T-G
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2
The NM_001167617.3(MLH1):c.12+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,585,538 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Consequence
NM_001167617.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000736 AC: 112AN: 152162Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00249 AC: 627AN: 251344Hom.: 11 AF XY: 0.00306 AC XY: 416AN XY: 135846
GnomAD4 exome AF: 0.00113 AC: 1621AN: 1433258Hom.: 25 Cov.: 26 AF XY: 0.00157 AC XY: 1122AN XY: 714766
GnomAD4 genome AF: 0.000742 AC: 113AN: 152280Hom.: 4 Cov.: 32 AF XY: 0.00106 AC XY: 79AN XY: 74454
ClinVar
Submissions by phenotype
not specified Benign:5Other:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 06, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 15, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 04, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 20, 2016 | Variant summary: The c.303T>G (p.Gly101=) in MLH1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing which was supported by a RNA-based functional assay by Thompson et al (2012). The variant is present in the control population dataset of ExAC at frequency of 0.0027 (331/121138) predominantly in individuals of South Asian descent (0.02; 329/16482 chrs) including 5 homozygous occurrences, suggesting that it is a polymorphism mainly found in South Asian population. The variant of interest been reported in affected individuals in whom either another known pathogenic variant was identified (Internal LCA data) or ICH results pointed out mutation(s) in other MMR genes (Mangold, 2007). In addition, the variant is cited as Benign/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant is classified as Benign. - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Colorectal cancer, hereditary nonpolyposis, type 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 22, 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). 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. - |
Lynch syndrome Benign:2
Likely benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Synonymous substitution with no effect on splicing & MAF 0.01-1% - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MLH1 p.Gly101Gly was identified in 1 of 20 proband chromosomes (frequency: 0.05) from individuals with Muir-Torre syndrome (Mangold 2007). The variant was also identified in dbSNP (ID: rs4647220) “With other allele”, in the 1000 Genomes Project in 32 of 5000 chromosomes (frequency: 0.0064) and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 336 of 16482 chromosomes (frequency: 0.02) (or 329 individuals and 5 homozygous individuals) from a population of South Asian individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in Clinvitae database (2x), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (2X), the ClinVar database (classified as a likely benign by an expert panel), and UMD (1X as an unknown variant). The p.Gly101Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence, 4th base from the 5' splice region, and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing leading to the loss of a predicted splice site at a non-consensus splice site location; we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site however this information is not predictive enough to assume pathogenicity. Thompson et al. (2013) assessed MMR (mismatch repair) variants using multifactorial analysis, prior probabilities and likelihood ratios, as well as in vitro splicing assays and found the variant to be Class 3, uncertain significance, and having wildtype splicing. The identification of this variant in an individual with a co-occurring pathogenic variant (MSH2, c.1-?_366+?del) from our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign. - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 23, 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 23, 2015 | - - |
Breast and/or ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 14, 2021 | - - |
Muir-Torré syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Feb 01, 2025 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 02, 2025 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at