ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
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 likely benign not provided 2020-11-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28466842, 25986311, 27930734, 26333163, 17453009, 19224586, 19389263, 22843852, 27150160, 18383312, 16203774, 23729658, 15520370, 22875147, 17117178, 18033691, 25559809, 25871441, 22949387, 30680046)
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 2020-12-04 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 Health, Inc 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 2021-05-01 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358637 SCV001554430 likely benign Malignant tumor of breast no assertion criteria provided clinical testing MLH1, EXON1, c.65G>C, p.Gly22Ala, Heterozygous, Likely Benign The MLH1 p.Gly22Ala variant was identified in 4 of 2434 proband chromosomes (frequency: 0.002) from individuals with Lynch syndrome, colorectal cancer, or synchronous or metachronous adenomatous polyps, and was present in 3 of 3068 control chromosomes (frequency: 0.001) from healthy individuals (Fearnhead 2004, Woods 2005, Overbeek 2007, Barnetson 2008). The variant was identified in dbSNP (rs41295280) as “with uncertain significance allele”, ClinVar (classified as benign by an InSiGHT expert panel and Invitae; as likely benign by Ambry Genetics and Color; and as uncertain significance by GeneDx and 5 other submitters), UMD-LSDB (observed 5x as neutral and co-occurring with pathogenic mutations: MLH1, c.571-573delCTC, p.Leu191del and MLH1, c.1585delG, p.Glu529LysfsX14). The variant was identified in control databases in 35 of 277,150 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,034 chromosomes (freq: 0.0002), Other in 2 of 6466 chromosomes (freq: 0.0003), Latino in 1 of 34,420 chromosomes (freq: 0.00003), European in 28 of 126,644 chromosomes (freq: 0.0002), but it was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was also identified in a patient with a pathogenic variant in MSH6 (c.814G>T, p.Glu272X) and an MSH6-deficient endometrial tumour (Overbeek 2007). The p.Gly22 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000656857 SCV001808946 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000656857 SCV001923761 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000656857 SCV001954959 uncertain significance not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.