Submissions for variant NM_000249.4(MLH1):c.885-2A>G

dbSNP: rs267607805

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075914	SCV000106934	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000132040	SCV000187099	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-10-09	criteria provided, single submitter	clinical testing	The c.885-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the MLH1 gene. This alteration has been previously reported in an individual from a high-risk colorectal family with a MSI-high colorectal tumor (Terdiman JP et al. Gastroenterology. 2001; 120:21-3). This variant was also identified in an individual diagnosed with early-onset MSI-H colorectal cancer that demonstrated absent MLH1/PMS2 expression on immunohistochemistry (IHC) (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration weakens the native acceptor splice site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000627716	SCV000284080	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome and a Lynch syndrome-associated cancer (PMID: 11208710; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as IVS10-2A>G. ClinVar contains an entry for this variant (Variation ID: 90421). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000481722	SCV000571393	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30264478, 11208710, 26648449, 28152038, 30729418, 30787465)
Color Diagnostics, LLC DBA Color Health	RCV000132040	SCV000908615	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 10 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. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 11208710, 30729418). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481722	SCV001470544	pathogenic	not provided	2020-07-16	criteria provided, single submitter	clinical testing	The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Myriad Genetics, Inc.	RCV003452786	SCV004188188	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	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.
Baylor Genetics	RCV003452786	SCV004193052	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-04-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075914	SCV004847551	pathogenic	Lynch syndrome	2019-04-02	criteria provided, single submitter	clinical testing	The c.885-2A>G variant in MLH1 has been reported in 2 individuals with Lynch syndrome-related cancers (Clarke 2019, Terdiman 2001). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 90421). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MLH1 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.