ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.80G>A (p.Arg27Gln) (rs138705565)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197307 SCV000254372 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 27 of the MLH1 protein (p.Arg27Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs138705565, ExAC 0.003%). This variant has been observed in individuals with colorectal cancer and breast cancer (PMID: 25503501, 30729418). However, in one of these individuals, a pathogenic allele was also identified in MLH1, which suggests that this c.80G>A variant may not be the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 216337). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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.
GeneDx RCV000587717 SCV000279261 uncertain significance not provided 2020-08-25 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with breast cancer or colorectal cancer and co-occurred with an MLH1 canonical splice variant (Maxwell 2014, Clarke 2019); This variant is associated with the following publications: (PMID: 22949387, 22290698, 25503501, 30729418, 32123317)
Ambry Genetics RCV000573727 SCV000662012 likely benign Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification
Color Health, Inc RCV000573727 SCV000689923 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587717 SCV000696182 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.80G>A (p.Arg27Gln) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the histidine kinase-like ATPase, C-terminal domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000165 (2/121156 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). The variant has been reported in a patient with early onset breast cancer without strong evidence for or against pathogenicity (Maxwell_Genet Med_2014). In addition, multiple clinical diagnostic laboratories have classified this variant as one of uncertain significance. Taken together, this variant is classified as a VUS.
Counsyl RCV000662868 SCV000785757 uncertain significance Lynch syndrome II 2017-11-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587717 SCV000889404 uncertain significance not provided 2019-03-21 criteria provided, single submitter clinical testing

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