ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.808A>G (p.Thr270Ala) (rs371302926)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215834 SCV000273633 likely benign Hereditary cancer-predisposing syndrome 2017-10-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000215834 SCV000910976 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000412189 SCV000489683 uncertain significance Lynch syndrome II 2016-11-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000505929 SCV000919650 uncertain significance not specified 2018-07-02 criteria provided, single submitter clinical testing Variant summary: MLH1 c.808A>G (p.Thr270Ala) results in a non-conservative amino acid change located in the N-terminal DNA mismatch repair protein family domain and DNA mismatch repair protein, S5 domain 2-like domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 246228 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.808A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including VUS (3x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000475873 SCV000543644 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 270 of the MLH1 protein (p.Thr270Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs371302926, ExAC 0.03%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 230184). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505929 SCV000601412 uncertain significance not specified 2016-10-18 criteria provided, single submitter clinical testing

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