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

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130401	SCV000185261	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: 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
Color	RCV000130401	SCV000537451	likely benign	Hereditary cancer-predisposing syndrome	2015-04-27	criteria provided, single submitter	clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia	RCV000075527	SCV000257651	uncertain significance	Lynch syndrome	2015-05-14	criteria provided, single submitter	clinical testing
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.
Integrated Genetics/Laboratory Corporation of America	RCV000254664	SCV000696145	benign	not specified	2019-04-29	criteria provided, single submitter	clinical testing	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.
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
Invitae	RCV000524275	SCV000284046	benign	Hereditary nonpolyposis colon cancer	2018-01-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587809	SCV000889398	benign	not provided	2017-10-20	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