ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.207+5G>A

dbSNP: rs587781518
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001189837 SCV001357203 likely pathogenic Hereditary cancer-predisposing syndrome 2020-12-02 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the +5 position of intron 2 of the MLH1 gene. A functional RNA study has shown that this variant causes the out-of-frame skipping of exon 2, resulting in premature truncation (LOVD (https://databases.lovd.nl/shared/variants/0000426800#00013676) and external lab communication). This variant has been observed in an individual affected with bowel cancer that exhibited microsatellite instability (LOVD individual#00188772 and external lab communication). A similar variant, c.207+5G>C, has also been reported in individuals affected with colorectal cancer (PMID: 27978560, 32620519) and to cause the same RNA splicing defect (PMID: 27978560). 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.
Ambry Genetics RCV001189837 SCV002729769 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-13 criteria provided, single submitter clinical testing The c.207+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 2 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. This variant has been identified in an individual who was diagnosed with early-onset colon cancer that showed high microsatellite instability (MSI-H) (Fokkema IF et al. Hum. Mutat., 2011 May;32:557-63). This variant was also identified as somatic in a MSI-H colon tumor that displayed loss of both MLH1/PMS2 on immunohistochemistry (IHC) with MLH1 copy-neutral loss of heterozygosity (CN-LOH) and MLH1 promoter hypermethylation was absent (Ambry internal data). Another alteration at the same nucleotide position,c.207+5G>C, has been classified as likely pathogenic based on RNA studies demonstrating abnormal splicing with out-of-frame exon 2 skipping resulting in a premature stop codon, co-segregation with disease, and being identified in a patient meeting clinical diagnostic criteria for Lynch syndrome (Pearlman R et al. JAMA Oncol. 2017;3(4):464-471; Ambry internal data). Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by BDGP. RT-PCR using patient-derived RNA from a c.207+5G>A carrier was also reported to result in out-of-frame exon 2 skipping (Fokkema IF et al. Hum. Mutat., 2011 May;32:557-63). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV003594118 SCV004337886 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-15 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 926930). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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