ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.319A>G (p.Ile107Val) (rs572906317)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167889 SCV000218535 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 107 of the MLH1 protein (p.Ile107Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs572906317, ExAC 0.009%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 188068). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Ile170Arg) has been determined to be pathogenic (PMID: 16083711, 8776590, 21120944, 11793442, 11555625, 17510385, 12810663). This suggests that the isoleucine residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. 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.
GeneDx RCV000586116 SCV000569868 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.319A>G at the cDNA level, p.Ile107Val (I107V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ile107Val was not observed at a significant frequency in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ile107Val occurs at a position that is conserved across species and is located in the ATP-binding and hydrolysis domain (Raevaara 2005, Kansikas 2011). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may create a cryptic donor site upstream of the natural splice donor site for exon 4 and possibly lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MLH1 Ile107Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000583427 SCV000689879 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586116 SCV000696161 uncertain significance not provided 2016-04-01 criteria provided, single submitter clinical testing Variant summary: The c.319A>G variant affects a conserved nucleotide resulting in amino acid change from Ile to Val. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 1/121398 control chromosomes at a frequency of 0.0000082, which does not exceed the maximal expected frequency of a pathogenic allele (0.0007105). In addition, one clinical laboratory classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor was it evaluated for functional impact by in vivo/vitro studies. Due to the absence of clinical information and lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

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