ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.885-2A>G (rs267607805)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075914 SCV000106934 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000132040 SCV000187099 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-09 criteria provided, single submitter clinical testing ​The c.885-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the MLH1 gene. This alteration has been previously reported in an individual from a high-risk colorectal family with a MSI-high colorectal tumor (Terdiman JP et al. Gastroenterology. 2001; 120:21-3). This variant was also identified in an individual diagnosed with early-onset MSI-H colorectal cancer that demonstrated absent MLH1/PMS2 expression on immunohistochemistry (IHC) (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration weakens the native acceptor splice site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000627716 SCV000284080 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-05-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with Lynch syndrome (PMID: 11208710), and as de novo in an individual affected with a Lynch syndrome-associated cancer (Invitae). This variant is also referred to as IVS10-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 90421). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000481722 SCV000571393 pathogenic not provided 2020-11-16 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 30264478, 11208710, 26648449, 28152038, 30729418)
Color Health, Inc RCV000132040 SCV000908615 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-03 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 10 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 11208710, 30729418). 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 Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481722 SCV001470544 pathogenic not provided 2020-07-16 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.

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