Submissions for variant NM_000249.4(MLH1):c.207+1G>A

gnomAD frequency: 0.00001  dbSNP: rs267607718

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075505	SCV000106501	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000128866	SCV000172723	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	clinical testing	The c.207+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the MLH1 gene. This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including those whose tumors demonstrated high microsatellite instability and/or loss of MHL1 and PMS2 protein staining by immunohistochemistry (IHC) (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Yang M et al. Ther Adv Med Oncol, 2021 Jun;13:17588359211023290; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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 a disease-causing mutation.
Invitae	RCV000627707	SCV000284045	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 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 individuals with clinical features of Lynch syndrome (PMID: 16142001, 27978560; Invitae). ClinVar contains an entry for this variant (Variation ID: 90020). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202020	SCV000568563	pathogenic	not provided	2023-07-21	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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27978560, 21286823, 15849733, 24763289, 26648449, 30877237, 29750335, 30787465, 34178123, 31742824)
Color Diagnostics, LLC DBA Color Health	RCV000128866	SCV001340138	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-11-05	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the +1 position of intron 2 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 performed for this variant. This variant has been reported in individuals affected with Lynch Syndrome and colorectal cancer (PMID: 27978560, 29750335). 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. Based on the available evidence, this variant is classified as Likely Pathogenic.
Sema4, Sema4	RCV000128866	SCV002528711	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003451099	SCV004190041	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-14	criteria provided, single submitter	clinical testing	This variant is considered 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. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003451099	SCV004193038	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-08-13	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202020	SCV000257084	likely pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202020	SCV000592338	pathogenic	not provided		no assertion criteria provided	clinical testing	The c.207+1G>A variant has not been identified previously. The c.207+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant 1 and +2 positions region of the splice consensus sequence. Another variant at the same splice site (c.207+1G>T) has also been described to have splicing defect (Mangold 2005). In summary, based on the above information, this variant is classified as pathogenic.