ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.883A>C (p.Ser295Arg) (rs63751598)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075901 SCV000106917 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant allele results in splicing abberation leading to premature stop codon: full inactivation of variant allele
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075901 SCV000592385 pathogenic Lynch syndrome 2012-07-05 criteria provided, single submitter clinical testing
Invitae RCV001046252 SCV001210147 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 295 of the MLH1 protein (p.Ser295Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Lynch syndrome cancers (PMID: 20223024, 16451135, 16830052, 18772310, 18618713). ClinVar contains an entry for this variant (Variation ID: 90408). 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. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 20223024). 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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