rs759680369
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP5BP4BP7
The NM_000249.4(MLH1):c.27G>A(p.Arg9Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
MLH1
NM_000249.4 synonymous
NM_000249.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.73
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-36993574-G-A is Pathogenic according to our data. Variant chr3-36993574-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186982.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=5}.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36). . Strength limited to SUPPORTING due to the PP5.
BP7
Synonymous conserved (PhyloP=1.73 with no splicing effect.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 25, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 07, 2024 | The MLH1 c.27G>A (p.Arg9=) synonymous variant has been reported in the published literature along with low-level constitutional MLH1 promoter methylation in families with colorectal cancer (PMID: 29790873 (2018), 22878509 (2013)). This variant along with MLH1 promoter methylation has also been reported in an individual with colorectal cancer and endometrial cancer that showed microsatellite instability and loss of MLH1 and PMS2 protein expression (PMID: 29790873 (2018)). In addition, this variant has been reported in individuals with early onset colon cancer, breast cancer, and with a family history of Lynch syndrome associated cancers (personal communication with Ambry Genetics and Invitae related to ClinVar ID: 186982). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MLH1 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 05, 2024 | - - |
Hereditary nonpolyposis colon cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2024 | Variant summary: MLH1 c.27G>A alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251448 control chromosomes. c.27G>A has been reported in the literature in multiple individuals from a family affected with colorectal cancer (Leclerc_2018, Ward_2013). This variant also co-occurred with two pathogenic variants in CHEK2 and HOXB13 in a patient with multiple cancers including colon cancer, ovarium cancer, endometrium cancer and and CLL (Wallander_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29790873, 34711244, 22878509). ClinVar contains an entry for this variant (Variation ID: 186982). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 20, 2024 | This sequence change affects codon 9 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome-associated tumors and Lynch syndrome (PMID: 22878509, 29790873; internal data). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 186982). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2024 | The c.27G>A variant (also known as p.R9R), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide position 27. This nucleotide substitution does not change the arginine at codon 9. This alteration was detected along with low-level constitutional MLH1 promoter methylation in a Caucasian male with 3 colorectal cancers, one of which demonstrated high microsatellite instability (MSI-H) with loss of MLH1 protein expression on immunohistochemistry (IHC). The father and mother of this proband were both diagnosed with colorectal cancer as well as a son, who died at age 22 from colorectal cancer. The son also carried the c.27G>A variant allele along with low-level constitutional MLH1 promoter methylation; however, two affected maternal family members did not carry this alteration and were negative for constitutional MLH1 promoter methylation indicating the variant allele may have been paternally inherited (Ward RL et al. Genet. Med. 2013 Jan;15:25-35). This alteration was also reported in a French family that fulfilled Amsterdam I criteria and exhibited low-level constitutional MLH1 promoter methylation. Four family members, two diagnosed with colorectal cancer and two with colorectal adenomas, carried the c.27G>A allele along with low-level constitutional MLH1 promoter methylation. This alteration was identified in another unrelated individual in this study who was diagnosed with colorectal cancer as well as endometrial cancer and had constitutional MLH1 promoter methylation (Leclerc J et al. Genet. Med. 2018 12;20:1589-1599). In our clinical cohort, this alteration also segregated with low-level constitutional MLH1 promoter methylation and disease in families meeting clinical diagnostic criteria for Lynch syndrome (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at