ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1558+5G>A (rs199935667)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590226 SCV000149370 uncertain significance not provided 2021-04-12 criteria provided, single submitter clinical testing In silico analysis supports a deleterious effect on splicing; Observed in a family fulfilling Amsterdam criteria II for Lynch syndrome (Tang 2009); This variant is associated with the following publications: (PMID: 25525159, 26332594, 19419416, 30093976, 29887214)
Ambry Genetics RCV000115461 SCV000218331 likely benign Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing No disease association in small case-control study;Other data supporting benign classification
Invitae RCV001086042 SCV000259283 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515436 SCV000611398 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115461 SCV000684754 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-20 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 and gastric cancer and a suspected Lynch syndrome family (PMID: 10861474, 19419416, 30093976). 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 Lynch syndrome II 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 Praxis fuer Humangenetik Tuebingen RCV000590226 SCV001748064 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing

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