ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.-7C>T (rs104894994)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114845 SCV000149357 uncertain significance not provided 2018-11-09 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.-7C>T, and describes a nucleotide substitution 7 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 CTGG[C/T]GCCA. According to the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database, MLH1 c.-7C>T is an uncertain variant based on insufficient evidence and has been reported to co-occur with MLH1 c.-28A>G in individuals with a personal and/or family history suggestive of Lynch syndrome, as well as in a hereditary prostate cancer family (Fredriksson 2006, Thompson 2014, Hesson 2015, Lagerstedt-Robinson 2016). In one study of two such individuals from suspected Lynch syndrome families, these variants conferred an approximate 50% reduction in MLH1 expression, although there was no MLH1 promoter methylation and the promoter remained epigenetically unaltered (Hesson 2015). MLH1 c.-7C>T has also been reported with MLH1 c.-28A>G in individuals with colon cancer whose tumors were reportedly not suggestive of Lynch syndrome (Morak 2018). Although this variant does not appear to affect the start codon or the Kozak translational consensus sequence, 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 2011, Ward 2013). This variant was observed at an allele frequency of 0.80% (207/25788) in individuals of Finnish ancestry in large population cohorts (Lek 2016). At this time, we consider MLH1 c.-7C>T to be a variant of uncertain significance.
Invitae RCV000075068 SCV000259816 benign Lynch syndrome 2016-02-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776038 SCV000910640 benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000115448 SCV001339157 benign not specified 2020-03-05 criteria provided, single submitter clinical testing Variant summary: MLH1 c.-7C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0013 in 251462 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.8- fold the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Non-Polyposis Colon Cancer phenotype (0.00071), strongly suggesting that the variant is benign. c.-7C>T has been reported in the literature in individuals affected with Hereditary Non-Polyposis Colon Cancer (examples-Hesson_2015, Lagerstedt-Robinson_2016). The variant has also been detected in individuals reported to have hereditary prostate cancer (Fredriksson_2006) and non-HNPCC cancer phenotypes (Morak_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. One publication reports experimental evidence suggesting that the variant results in a 50% reduction in MLH1 expression,however, does not allow convincing conclusions about the variant effect (Hesson_2015). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They cited the variant as benign (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV001511076 SCV001718259 benign Hereditary nonpolyposis colorectal neoplasms 2020-08-07 criteria provided, single submitter clinical testing
Harris Lab, University of Minnesota RCV000114845 SCV000148740 not provided not provided no assertion provided not provided
Mayo Clinic Laboratories, Mayo Clinic RCV000115448 SCV000691840 uncertain significance not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357193 SCV001552580 likely benign Carcinoma of colon no assertion criteria provided clinical testing The MLH1 c.-7C>T variant was identified in 2 of 980 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Fredriksson 2006, Lagerstedt-Robinson 2016). The variant was also identified in dbSNP (ID: rs104894994) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as uncertain significance by GeneDx, InSight and Mayo Clinic), and in LOVD 3.0 (11x). The variant was not identified in UMD-LSDB database. The variant was identified in control databases in 357 of 277232 chromosomes (3 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 13 of 6464 chromosomes (freq: 0.002), Latino in 3 of 34418 chromosomes (freq: 0.00009), European in 132 of 126720 chromosomes (freq: 0.001), Finnish in 207 of 25788 chromosomes (freq: 0.008), and South Asian in 2 of 30782 chromosomes (freq: 0.00007), but not in the African, Ashkenazi Jewish, or East Asian populations. One study by identified that the c.-7C>T variant was associated with partial constitutional loss of MLH1 expression and suggests it is the most likely cause of predisposition to CRC with MMR deficiency and loss of MLH1 (Hesson 2015). However, the same study confirmed the variant co-segregated on the same chromosome with MLH1 c.1164del (predicted to cause a frameshift) in one of the tested probands, increasing the likelihood that the variant does not have clinical significance (Hesson 2015). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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