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

Total submissions: 12

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.
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
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 colon cancer	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