ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1558+5G>A

gnomAD frequency: 0.00008  dbSNP: rs199935667
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590226 SCV000149370 uncertain significance not provided 2023-06-07 criteria provided, single submitter clinical testing Observed in a family fulfilling Amsterdam criteria II for Lynch syndrome (Tang et al., 2009); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 26332594, 30093976, 29887214, 26053027, 32363481, 19419416, 10861474)
Ambry Genetics RCV000115461 SCV000218331 likely benign Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Invitae RCV001086042 SCV000259283 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-21 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000515436 SCV000611398 uncertain significance Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 2017-05-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115461 SCV000684754 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-18 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +5 position of intron 13 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with ovarian cancer (PMID: 30093976) and gastric cancer (PMID: 10861474), as well as in a family that met Amsterdam criteria II for Lynch syndrome (PMID: 19419416). This variant also has been identified in 36/282692 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175375 SCV000696115 uncertain significance not specified 2019-10-21 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1558+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict that the variant weakens a 5' donor site. Two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251300 control chromosomes, predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2-fold over the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1558+5G>A, has been reported in the literature in individuals affected with Lynch Syndrome (Tang 2009, Kamiza 2015) and other tumor phenotypes (Bevilacqua 2000, Chan 2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submissions (evaluation after 2014) cite the variant five times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Counsyl RCV000663109 SCV000786227 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2018-03-23 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000758646 SCV000887407 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1558+5G>A has a 59.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
CeGaT Center for Human Genetics Tuebingen RCV000590226 SCV001748064 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003149796 SCV003838212 uncertain significance Breast and/or ovarian cancer 2022-05-31 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000663109 SCV004018145 benign Colorectal cancer, hereditary nonpolyposis, type 2 2023-03-14 criteria provided, single submitter clinical testing This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001175375 SCV004024909 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590226 SCV004220077 uncertain significance not provided 2022-05-19 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.0012 (24/19952 chromosomes in East Asian subpopulation,, is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in a Taiwanese family with Lynch syndrome (PMID: 19419416 (2009)), as well as in an individual with ovarian cancer (PMID: 30093976 (2018)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MLH1 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.

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