ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2101C>A (p.Gln701Lys) (rs63750114)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075527 SCV000106524 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Co-occurrence without CMMRD phenotype & MAF 0.01-1%. Multifactorial likelihood analysis posterior probability 0.001-0.049
Ambry Genetics RCV000130401 SCV000185261 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
GeneDx RCV000254664 SCV000211150 likely benign not specified 2017-12-21 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000075527 SCV000257651 uncertain significance Lynch syndrome 2015-05-14 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490357 SCV000267396 uncertain significance Lynch syndrome II 2016-03-18 criteria provided, single submitter reference population
Invitae RCV001086186 SCV000284046 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000130401 SCV000537451 likely benign Hereditary cancer-predisposing syndrome 2015-04-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000254664 SCV000696145 benign not specified 2019-04-29 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2101C>A (p.Gln701Lys) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of the encoded protein sequence that is necessary for interaction with PSM2 (Fan_2007). Three of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0005 in 251174 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0066 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. This variant has been reported in multiple sequencing studies among individuals of East Asian ancestry with a variety of cancers to include, Lynch Syndrome, biliary tract cancer and colon cancer (Zhi_2011, Talseth-Palmer_2016, Chan_2018, Kim_2017, Wardell_2018). Thus, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In addition, at-least one co-occurrence with the other potentially pathogenic variant (MLH1 c.208-1G>A) has been reported, providing supporting evidence for a benign role (Sheng_2008). A functional study demonstrated the variant to retain about 70% of its ability to interact with PMS2 (Fan_2007). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS (n=2), likely benign (n=2), and benign (n=2)). One expert panel (InSiGHT) has submitted clinical-significance assessment for this variant to ClinVar before 2014 and classified the variant as likely benign. As all of the evidence outlined above, spanning over a decade supports a non-pathogenic outcome, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587809 SCV000889398 benign not provided 2017-10-20 criteria provided, single submitter clinical testing
Mendelics RCV000490357 SCV001136435 benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000490357 SCV001307915 uncertain significance Lynch syndrome II 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093671 SCV001250852 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing

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