Submissions for variant NM_000249.4(MLH1):c.543C>T (p.Gly181=)

dbSNP: rs1481129490

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000782000	SCV000920460	pathogenic	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Variant creates de novo donor leading to a 4 bp deletion at the end of exon 6 in MLH1
Ambry Genetics	RCV001024107	SCV001186066	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-07	criteria provided, single submitter	clinical testing	The c.543C>T variant (also known as p.G181G), located in coding exon 6, results from a C to T substitution at nucleotide position 543 of the MLH1 gene. This nucleotide substitution does not change the amino acid at codon 181. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site. This variant has been identified in a patient with metachronous colon cancers at 55y & 59y whose tumor demonstrated microsatellite instability (MSI-H) and MLH1/PMS2 deficiency on IHC. RNA analysis revealed an abnormal transcript caused by c.543C>T containing a 4-bp deletion and leading to premature protein truncation (p.G181Gfs*20) in a high percentage (30%) of total reads (Yamaguchi T et al. Jpn. J. Clin. Oncol., 2017 Jun;47:576-580). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001024107	SCV001344851	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-29	criteria provided, single submitter	clinical testing	This synonymous variant does not change the amino acid sequence of the MLH1 protein. However, splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has shown that this variant causes deletion of the last 4 nucleotides of exon 6, creating a premature translation stop signal in the MLH1 RNA transcript (PMID: 28334867). The aberrant RNA transcript is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal cancer (PMID: 28334867) and endometrial cancer (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003453615	SCV004185772	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28334867].