rs267607735
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.306+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,407,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000249.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000284 AC: 4AN: 1407220Hom.: 0 Cov.: 25 AF XY: 0.00000426 AC XY: 3AN XY: 703416
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | research | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2025 | Common founder variant in the Spanish population (PMID: 20858721); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 19760518, 23523604); Intronic +5 splice variant in a gene for which loss-of-function is a known mechanism of disease, demonstrated to result in impaired splicing and aberrant transcript (PMID: 19250818; 20858721); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21778331, 22864660, 19250818, 25525159, 16142001, 28874130, 19760518, 24344984, 23554159, 25345868, 21972078, 16083711, 21120944, 22753075, 20858721, 23523604) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 31, 2023 | The c.306+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 3 in the MLH1 gene. This mutation has been identified in numerous families fulfilling Amsterdam I/II criteria and in individuals with tumors demonstrating high microsatellite instability (MSI-H) and/or loss of MLH1/PMS2 protein expression on immunohistochemistry (IHC) (Borras et al. Cancer Res 2010 Oct 1; 70(19):7379-91; Perez-Cabornero et al. Eur J Cancer 2009 May; 45(8): 1485-93, Pérez-Cabornero et al. J Mol Diagn 2013 May;15(3):380-90; Rossi BM et al. BMC Cancer, 2017 Sep;17:623, Ambry internal data). RNA analyses by these authors have demonstrated that this mutation generates an aberrant mRNA transcript resulting in premature protein truncation. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Haplotype analysis supports c.306+5G>A as a founder mutation of Spanish origin (Borras et al. Cancer Res 2010 Oct 1; 70(19):7379-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 02, 2021 | This variant causes a G to A nucleotide substitution at the +5 position of intron 3 of the MLH1 gene. Functional RNA studies have shown that this variant causes use of a cryptic site in exon 3 resulting in premature truncation. This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 16142001, 19760518, 20858721, 23523604, 28874130) and is a common pathogenic variant in people of Spanish ancestry. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2010 | - - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Lynch syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Variant causes splicing aberration leading to truncated protein, >2 MSI-H tumours, co-segregation with disease & MAF 0.0 - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 06, 2024 | This sequence change falls in intron 3 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome (PMID: 16142001, 23523604, 28874130). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS3+5G>A. ClinVar contains an entry for this variant (Variation ID: 90148). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MLH1 function (PMID: 19250818). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Lynch syndrome 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at