ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2173C>G (p.Arg725Gly) (rs138584384)

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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 RCV000217046 SCV000273152 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000663259 SCV000786487 uncertain significance Lynch syndrome II 2018-05-11 criteria provided, single submitter clinical testing
Invitae RCV000461789 SCV000543651 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 725 of the MLH1 protein (p.Arg725Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID:25503501). ClinVar contains an entry for this variant (Variation ID: 229812). 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.

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