ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.974G>A (p.Arg325Gln)

gnomAD frequency: 0.00002  dbSNP: rs63750268
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075949 SCV000106968 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics RCV000163500 SCV000214058 likely benign Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV001081578 SCV000253148 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000216577 SCV000279335 likely benign not specified 2017-10-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000409264 SCV000488009 likely benign Colorectal cancer, hereditary nonpolyposis, type 2 2015-12-11 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000216577 SCV000595808 likely benign not specified 2017-04-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000524326 SCV000601420 likely benign not provided 2020-09-09 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000163500 SCV000910960 likely benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000216577 SCV000917656 uncertain significance not specified 2021-08-19 criteria provided, single submitter clinical testing Variant summary: MLH1 c.974G>A (p.Arg325Gln) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251356 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 0.00071), allowing no conclusion about variant significance. c.974G>A has been reported in the literature in individuals affected with Lynch Syndrome, including two families in which the variant appears to segregate with disease (two affected patients per family carrying the variant; Borras_2012, Castillejo_2014). Additionally, the variant was reported in MSI-high cancers, without strong evidence for causality (Deihimi_2017, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Suggesting a benign impact, functional studies including splicing assay, MMR assay, MLH1 expression and PMS2 expression, and MLH1 and PMS2 subcellular localization show the variant to have function similar to WT (Borras_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
Sema4,Sema4 RCV000163500 SCV002528791 likely benign Hereditary cancer-predisposing syndrome 2021-06-27 criteria provided, single submitter curation

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