Submissions for variant NM_000249.4(MLH1):c.884G>C (p.Ser295Thr)

dbSNP: rs63750144

Total submissions: 3

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	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-27	criteria provided, single submitter	clinical testing	This sequence change affects codon 295 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Lynch Syndrome (PMID: 9399661). It has also been observed to segregate with disease in related individuals. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26761715). This variant disrupts the c.884G nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12200596, 22949379, 26761715). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452785	SCV004185628	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15713769, 18561205, 16395668, 17653898].