ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1553A>G (p.His518Arg) (rs1182262731)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564821 SCV000669618 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-16 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000630203 SCV000751159 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-03-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 518 of the MLH1 protein (p.His518Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. 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: 483592). 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: "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. 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 RCV000564821 SCV000913049 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing

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