ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.884G>C (p.Ser295Thr) (rs63750144)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075909 SCV000106926 uncertain significance Lynch syndrome 2018-06-13 reviewed by expert panel curation G>non-G at last base of exon with first 6 intronic bases not GTRRGT; Insufficient evidence
Invitae RCV000630082 SCV000751038 likely pathogenic Hereditary nonpolyposis colon cancer 2017-09-01 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 295 of the MLH1 protein (p.Ser295Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. 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. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family with hereditary non-polyposis colon cancer (PMID: 9399661) and it has been reported in individuals in the Universal Mutation Database (PMID:23729658) . ClinVar contains an entry for this variant (Variation ID: 90416). 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 missense change decreased exon 10 inclusion in a minigene assay (PMID: 26761715). A different missense substitution at this codon (p.Ser295Asn) has been determined to be pathogenic (PMID: 26761715, 12200596). This suggests that the serine residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Likely Pathogenic.

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