ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.144A>C (p.Gln48His) (rs147342421)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520645 SCV000616779 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.144A>C at the cDNA level, p.Gln48His (Q48H) at the protein level, and results in the change of a Glutamine to a Histidine (CAA>CAC). This variant has been identified in an individual with a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). MLH1 Gln48His was not observed in large population cohorts (Lek 2016). Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Gln48His occurs at a position that is conserved across species and is located in the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Gln48His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000543077 SCV000625068 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-10 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 48 of the MLH1 protein (p.Gln48His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs147342421, ExAC 0.01%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 449060). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The p.Gln48 amino acid residue in MLH1 has been determined to be clinically significant (PMID: 19386570, 21404117, 24362816, 22395473). This suggests that variants that disrupt this residue are likely to be causative of disease. 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 RCV000579927 SCV000684744 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing
Counsyl RCV000663271 SCV000786503 uncertain significance Lynch syndrome II 2018-05-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000579927 SCV001171984 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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