ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590226 SCV000149370 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1558+5G>A or IVS13+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 13 of the MLH1 gene. Multiple in silico models predict this variant to either damage or destroy the nearby natural splice donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This splice variant has been previously reported in one family fulfilling Amsterdam criteria II for Lynch syndrome (Tang 2009). MLH1 c.1558+5G>A was observed at an allele frequency of 0.1% (19/18868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MLH1 c.1558+5G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115461 SCV000218331 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001086042 SCV000259283 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 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 RCV000115461 SCV000684754 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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