ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.884G>A (p.Ser295Asn) (rs63750144)

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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) RCV000075908 SCV000106925 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
Ambry Genetics RCV000215143 SCV000277766 pathogenic Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Last nucleotide of exon;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV001220885 SCV001392898 pathogenic Hereditary nonpolyposis colon cancer 2019-07-17 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 295 of the MLH1 protein (p.Ser295Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 10 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with Lynch syndrome (PMID: 12200596). ClinVar contains an entry for this variant (Variation ID: 90415). Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 22949379, 26761715). For these reasons, this variant has been classified as Pathogenic.

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