ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.794G>A (p.Arg265His) (rs63751448)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524318 SCV000166257 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 265 of the MLH1 protein (p.Arg265His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs63751448, ExAC 0.006%). This variant has been reported in individuals and families affected with Lynch syndrome (PMID: 8993976, 18561205) as well as in the Universal Mutation Database (PMID: 23729658). However, in one of these individuals, this variant occurs with a likely pathogenic variant in MLH1 (PMID: 23729658). While it is unknown if these variants are on the same or opposite chromosomes, this observation suggests that the c.794G>A variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 90381). Experimental studies are conflicting with regards to the effect of this missense change on protein function, with several indicating that this variant has no effect on activity and others showing that it moderately impacts function (PMID: 11555625, 12810663, 23403630, 9697702, 17510385, 11781295, 20176959, 17210669). However, this variant was reported to disrupt mRNA splicing when examined in in vitro splicing assays (PMID: 18561205, 22736432, 26761715). In summary, this variant is a rare missense change with uncertain impact on RNA splicing and protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000131125 SCV000186056 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing Conflicting evidence
GeneDx RCV000656858 SCV000211097 uncertain significance not provided 2017-12-13 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.794G>A at the cDNA level, p.Arg265His (R265H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in at least two kindreds with Hereditary Nonpolyposis Colorectal Cancer, occurring on the same allele (in cis) with a truncating MLH1 variant in one family (Viel 1997, Tournier 2008). While multiple in vitro functional assays suggest this variant to be benign based on normal mismatch repair (MMR) function and protein expression (Shimodaira 1998, Kondo 2003, Takahashi 2007, Hinrichsen 2013), others showed that this variant results in partial exon skipping and/or partial loss of MMR function (Ellison 2001,Tournier 2008, Soukarieh 2016). MLH1 Arg265His was observed at an allele frequency of 0.005% (12/246232 alleles) in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. MLH1 Arg265His is located in the ATPase domain (Andersen 2012). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain" (Thompson 2014). Due to somewhat conflicting evidence regarding the clinical effect of this variant, we consider MLH1 Arg265His to be a variant of uncertain significance."
Counsyl RCV000410210 SCV000487858 uncertain significance Lynch syndrome II 2015-11-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212526 SCV000539646 uncertain significance not specified 2016-06-16 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: 13 papers in HGMD, however several of these call pathogenicity into question. ClinVar: 3 VUS (including expert panel - no new evidence since this classification), 1 LB
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212526 SCV000592380 uncertain significance not specified 2014-12-05 criteria provided, single submitter clinical testing
Color RCV000131125 SCV000910975 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212526 SCV000919666 uncertain significance not specified 2018-12-03 criteria provided, single submitter clinical testing Variant summary: MLH1 c.794G>A (p.Arg265His) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 246232 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (4.9e-05 vs 0.00071), allowing no conclusion about variant significance. c.794G>A has been reported in the literature in individuals affected with Lynch Syndrome (Pastrello_2011, Tournier_2008). Two families reported in Pastrello_2011, indicate the variant to co-occur with a pathogenic MLH1 variant, c.1011delC. In addition, one of the families showed the variant of interest to lack cosegregation with disease. Tournier_2008 also reports the variant to co-occur with another potentially pathogenic MLH1 variant, c.1989G>T (p.Glu663Asp). Several publications reporting experimental evidence with conflicting interpretations with some showing no impact of the variant on protein function and mismatch repair (MMR) activity, while others do report reduced MMR efficiency (Hinrichsen_2013, Borras_2012, Martinez_2010, Zhao_2008, Takahashi_2007, Wanat_2007, Kondo_2003, Trojan_2002, Ellison_2001, Shimodaira_1998). Furthermore, conflicting experimental evidence was observed in regards to RNA splicing with indications of varying levels of exon 10 skipping to no effect (Soukarieh_2016, Borras_2012, Pastrello_2011, Tournier_2008). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656858 SCV001134324 uncertain significance not provided 2018-12-21 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000131125 SCV000788026 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-01 no assertion criteria provided clinical testing

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