Submissions for variant NM_000249.4(MLH1):c.678-2A>G

dbSNP: rs587779035

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075815	SCV000106829	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000569823	SCV000662117	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-19	criteria provided, single submitter	clinical testing	The c.678-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the MLH1 gene. This variant has been identified in a proband who met Amsterdam II criteria for Lynch syndrome and tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). An external study reported that this alteration results in skipping of coding exon 9, leading to an out-of-frame transcript (Thompson BA et al. Hum Mutat, 2013 Jan;34:200-9). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000569823	SCV000908612	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-03	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 8 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Invitae	RCV001380125	SCV001578071	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-03-01	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: RQ1138090). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90324). This variant is not present in population databases (ExAC no frequency).
Myriad Genetics, Inc.	RCV003452761	SCV004189386	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.