Submissions for variant NM_000249.4(MLH1):c.882C>T (p.Leu294=)

dbSNP: rs63751707

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075900	SCV000106916	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	RCV000574927	SCV000676021	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	clinical testing	The c.882C>T pathogenic mutation (also known as p.L294L), located in coding exon 10, results from a C to T substitution at nucleotide position 882 of the MLH1 gene. This nucleotide substitution does not change the amino acid at codon 294. This alteration has been detected in an individual who met Amsterdam I criteria for Lynch syndrome and whose tumor demonstrated high microsatellite instability with loss of MLH1 protein expression by immunohistochemistry (Spaepen M et al. Fam. Cancer, 2006;5:179-89). This pathogenic mutation has also been reported in other Lynch syndrome families or those suspected of having Lynch syndrome (Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Chubb D et al. Nat Commun, 2016 06;7:11883; Dedeurwaerdere F et al. Sci Rep, 2021 Jun;11:12880). In silico splice site analysis for this alteration is inconclusive. RT-PCR performed using patient samples and minigene analyses demonstrate that this alteration results in out-of-frame CDS 10 skipping (Ambry internal data; Soukarieh O et al. PLoS Genet., 2016 Jan;12:e1005756; Tournier I et al. Hum. Mutat., 2008 Dec;29:1412-24; Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54; Spaepen M et al. Fam. Cancer, 2006;5:179-89; van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3(4):327-45). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000574927	SCV000689925	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-11-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759814	SCV000889407	likely pathogenic	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Invitae	RCV000818945	SCV000959584	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16395668, 16736289, 18561205, 26247049, 26761715). ClinVar contains an entry for this variant (Variation ID: 90407). This variant has been observed in individual(s) with Lynch syndrome (PMID: 16395668, 16736289, 18561205). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 294 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Myriad Genetics, Inc.	RCV003452781	SCV004188555	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 [Myriad internal data].