ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.-28A>G (rs56198082)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000662924 SCV000785872 likely benign Lynch syndrome II 2017-12-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000115447 SCV000592325 uncertain significance not specified 2015-04-08 criteria provided, single submitter clinical testing
GeneDx RCV000656855 SCV000149356 uncertain significance not provided 2018-09-07 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.-28A>G, and describes a nucleotide substitution 28 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 CTAG[A/G]CGTT. According to the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database, MLH1 c.-28A>G is an uncertain variant based on insufficient evidence and has been reported to co-occur with MLH1 c.-7C>T in individuals with a personal and/or family history suggestive of Lynch syndrome, as well as in a hereditary prostate cancer family (Lee 2005, Fredriksson 2006, Thompson 2014, Hesson 2015). In one study of two such individuals from suspected Lynch syndrome families, these variants conferred an approximate 50% reduction in MLH1 expression and were not associated with MLH1 promoter methylation (Hesson 2015). However, MLH1 c.-28A>G has not undergone independent functional interrogation. A case-control study found that MLH1 c.-28A>G does not increase the risk for gastric cancer in Chinese males and has also been observed in individuals with colon cancer whose tumors were reportedly not suggestive of Lynch syndrome (Zhi 2011, Morak 2018). This variant was observed at an allele frequency of 0.81% (208/25,792) in individuals of Finnish ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MLH1 c.-28A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075059 SCV000106613 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000075059 SCV000260936 benign Lynch syndrome 2016-03-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000115447 SCV000539630 benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.9% (58/6612) Finnish chromosomes
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000115447 SCV000691838 uncertain significance not specified no assertion criteria provided clinical testing
Mendelics RCV000075059 SCV000837989 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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