ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.-42C>T (rs41285097)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131249 SCV000186211 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000679261 SCV000211123 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.-42C>T, and describes a nucleotide substitution 42 base pairs upstream of the MLH1 ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is CTTC[C/T]GTTG. Of note, constitutional epigenetic silencing of MLH1 has been suggested as an alternate mechanism responsible for Lynch syndrome and variants located within the 5' UTR have been shown to result in allele specific promoter methylation and subsequent transcriptional silencing (Hitchins 2009, Ward 2013). This variant was observed in two individuals suspected of having Lynch syndrome, as well as in two individuals with colon cancer showing loss of MLH1 expression by immunohistochemistry (IHC) (Green 2003, Mangold 2005, Ward 2013, Yurgelun 2015, Morak 2018). While cDNA analysis in one of these individuals showed biallelic MLH1 expression (Morak 2018), this variant has also been associated with reduced promoter activity in experimental cell lines (Green 2003, Ward 213). MLH1 c.-42C>T was observed at an allele frequency of 0.01% (12/126682 alleles) in individuals of European ancestry in large population cohorts (Lek 2016). The cytosine (C) nucleotide that is altered is not conserved. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain (Thompson 2014). At this time, we consider MLH1 c.-42C>T to be a variant of uncertain significance.
Invitae RCV000524298 SCV000283993 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-08-04 criteria provided, single submitter clinical testing
Counsyl RCV000410786 SCV000488806 uncertain significance Lynch syndrome II 2016-06-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075062 SCV000592324 likely pathogenic Lynch syndrome 2012-11-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679261 SCV000805937 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825373 SCV000966668 uncertain significance not specified 2018-09-18 criteria provided, single submitter clinical testing The c.-42C>T variant in MLH1 has been reported in 5 individuals with colorectal cancer (Green 2003, Mangold 2005, Ward 2013, Yurgelun 2015, Morak 2018), and seg regated with disease in two individuals from 1 family (Green 2003). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 8959 3) and has also been identified in 0.01% (12/126682) of European chromosomes by gnomAD ( The c.-42C>T variant is located in th e 5' UTR, but its effect on translation is unknown. In vitro functional studies provide some evidence that it may impact protein function (Green 2003, Ward 2013 ). In summary, the clinical significance of the c.-42C>T variant is uncertain. A CMG/AMP Criteria applied: PS3_Supporting, PS4_Supporting.
OMIM RCV000410786 SCV000038908 pathogenic Lynch syndrome II 2003-09-01 no assertion criteria provided literature only

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