ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1309C>G (p.Pro437Ala) (rs587782273)

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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 RCV000131128 SCV000186060 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000588028 SCV000211103 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1309C>G at the cDNA level, p.Pro437Ala (P437A) at the protein level, and results in the change of a Proline to an Alanine (CCT>GCT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MLH1 Pro437Ala was not observed in large population cohorts (Lek 2016). MLH1 Pro437Ala is located in the region of interaction with EXO1 (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Pro437Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000556437 SCV000625056 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 437 of the MLH1 protein (p.Pro437Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 142163). 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.
Color RCV000131128 SCV000689802 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588028 SCV000696105 uncertain significance not provided 2017-02-13 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1309C>G (p.Pro437Ala) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121382 control chromosomes. It has been reported in one extrauterine Mllerian carcinoma sample without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, because of lack of clinical and functional data, this variant is classified as VUS.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000588028 SCV000885701 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing

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