Submissions for variant NM_000249.4(MLH1):c.1410-2A>G

dbSNP: rs746536721

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528881	SCV000625062	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-08-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 12 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs746536721, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with pancreatic cancer (PMID: 36139606). ClinVar contains an entry for this variant (Variation ID: 455386). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and exon 13 skipping, and produces a non-functional protein and/or introduces a premature termination codon (internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mendelics	RCV000987177	SCV001136413	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001011401	SCV001171717	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-06-10	criteria provided, single submitter	clinical testing	The c.1410-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 13 in the MLH1 gene. This variant was detected in 1/422 Italian pancreatic cancer patients (Puccini A et al. Cancers (Basel), 2022 Sep;14). 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 and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000987177	SCV001434904	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2019-06-17	criteria provided, single submitter	clinical testing	The c.1410-2A>G variant in canonical splice site of the MLH1 gene is predicted to result in abnormal splicing of MLH1 mRNA. This variant is extremely rare in general population databases. Therefore, this c.1410-2A>G variant is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001011401	SCV002052215	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-02-16	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a pancreatic cancer case-control study in population controls and absent in cases (PMID: 29922827) and in an individual who underwent whole-genome sequencing and was not selected for cancer phenotypes (PMID: 27930734). This variant has been identified in 3/251436 chromosomes 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.
GeneDx	RCV003228943	SCV003925906	likely pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Myriad Genetics, Inc.	RCV000987177	SCV004185594	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	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	RCV000987177	SCV004192962	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806403	SCV005427880	likely pathogenic	Lynch syndrome	2024-09-26	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 12 of the MLH1 gene. Splice site prediction tools predict 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 a pancreatic cancer case-control study in population controls and absent in cases (PMID: 29922827) and in an individual who underwent whole-genome sequencing and was not selected for cancer phenotypes (PMID: 27930734). This variant has been identified in 3/251436 chromosomes 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	RCV003228943	SCV005623552	pathogenic	not provided	2024-09-30	criteria provided, single submitter	clinical testing	The MLH1 c.1410-2A>G variant disrupts a canonical splice-acceptor site and interferes with normal MLH1 mRNA splicing. This variant has been reported in the published literature in an individual with pancreatic cancer (PMID: 36139606 (2022)). The frequency of this variant in the general population, 0.000026 (3/113722 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.