ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.299G>A (p.Arg100Gln) (rs63750266)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590561 SCV000149388 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.299G>A at the cDNA level, p.Arg100Gln (R100Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been observed in at least three patients with colorectal cancer, and was shown to slightly impair mismatch repair activity in a yeast-human cell hybrid assay (Ellison 2004, Hampel 2008, Bartley 2012, Shirts 2016). MLH1 Arg100Gln was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Arg100Gln occurs at a position that is conserved across species and is located in the ATP-binding and hydrolysis domain (Raevaara 2005, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Arg100Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115479 SCV000185074 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-11 criteria provided, single submitter clinical testing Insufficient evidence
University of Washington Department of Laboratory Medicine, University of Washington RCV000075618 SCV000266180 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000524288 SCV000284057 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 100 of the MLH1 protein (p.Arg100Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs63750266, ExAC 0.003%). This variant has been reported in individuals affected with colorectal cancer (PMID: 18809606) and colon cancer (PMID: 26845104, 22086678). ClinVar contains an entry for this variant (Variation ID: 90132). Experimental studies have shown that this missense change decreases MLH1 function in a mismatch repair assay in yeast (PMID: 15475387). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000412390 SCV000488458 uncertain significance Lynch syndrome II 2016-04-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212517 SCV000592345 uncertain significance not specified 2014-06-02 criteria provided, single submitter clinical testing
Color RCV000115479 SCV000684813 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590561 SCV000696158 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.299G>A (p.Arg100Gln) variant causes a missense change involving the alteration of a conserved nucleotide and it is located in the Histidine kinase-like ATPase, C-terminal domain (IPR003594). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). One functional study shows 34-66% loss of MMR function but was performed in hybrid human-yeast genes (Ellison_NAR_2004). The variant of interest has been found in a large, broad control population, ExAC in 2/121214 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). This variant was reported in CRC patients without strong evidence for causality and including discordant MSI and IHC results (Bartley_PMS2_CanPrevRes_2011, Hampel_MSH6_JClin Onc_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more definitive functional and clinical study results become available.
Fulgent Genetics,Fulgent Genetics RCV000764480 SCV000895551 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing

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