ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.65G>C (p.Gly22Ala) (rs41295280)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075796 SCV000106808 benign Lynch syndrome 2018-10-18 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability <0.001
GeneDx RCV000656857 SCV000149393 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.65G>C at the cDNA level, p.Gly22Ala (G22A) at the protein level, and results in the change of a Glycine to an Alanine (GGG>GCG). While this variant resulted in an increase in mutation rates via a yeast hybrid assay, it retained in-vivo protein levels similar to wild type and did not exhibit a dominant-negative effect (Bolz 2012). Three case-control series have not found convincing evidence that MLH1 Gly22Ala occurs more often in cases with either adenomatous polyps or colorectal cancer than in controls (Fearnhead 2004, Barnetson 2008, Lefevre 2012). Barnetson et al. (2008) reported microsatellite stability and intact MLH1 protein expression in the tumor from their case patient. Additionally, Kets et al. (2006) reported this variant to co-occur with a pathogenic MSH6 variant in an individual with an MSI-high endometrial cancer lacking MSH6 protein expression and family history of both colon and endometrial cancers. MLH1 Gly22Ala was observed at an allele frequency of 0.02% (28/126,644) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. MLH1 Gly22Ala is located in the ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available evidence, it is unclear whether MLH1 Gly22Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115484 SCV000172837 likely benign Hereditary cancer-predisposing syndrome 2018-05-18 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Invitae RCV001083728 SCV000253141 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000412464 SCV000488206 uncertain significance Lynch syndrome II 2016-01-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212512 SCV000539647 uncertain significance not specified 2016-06-23 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: ClinVar: 1 LB, 3 VUS (includes expert panel), no new evidence since expert classification
Mendelics RCV000075796 SCV000837991 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765727 SCV000897095 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000115484 SCV000902663 likely benign Hereditary cancer-predisposing syndrome 2015-12-09 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656857 SCV001153831 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115484 SCV000886685 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 no assertion criteria provided clinical testing

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