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	2024-09-20	criteria provided, single submitter	clinical testing	The c.543C>T variant (also known as p.G181G), located in coding exon 6 of the MLH1 gene, results from a C to T substitution at nucleotide position 543. This nucleotide substitution does not change the at codon 181. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MLH1/PMS2 expression by immunohistochemistry (Yamaguchi T et al. Jpn. J. Clin. Oncol., 2017 Jun;47:576-580). This variant has also been identified in at least one proband who met Amsterdam I criteria for Lynch syndrome and tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Yamaguchi T et al. Jpn. J. Clin. Oncol., 2017 Jun;47:576-580). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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].