Submissions for variant NM_000249.4(MLH1):c.2103+1G>T

dbSNP: rs267607888

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075531	SCV000106528	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Color Diagnostics, LLC DBA Color Health	RCV000446141	SCV000537620	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the canonical +1 position of intron 18 splice donor site 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 investigated in published RNA studies, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in ten individuals affected with Lynch syndrome (PMID: 15342696, 21671081, 27152634, 28195393, 31297992). 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 Pathogenic.
GeneDx	RCV000483619	SCV000568571	likely pathogenic	not provided	2021-06-08	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15342696, 25525159, 27247567, 27152634, 18772310, 27535533, 28195393, 12799449, 20533529, 22753075, 31297992)
Ambry Genetics	RCV000446141	SCV002724566	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	The c.2103+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 18 of the MLH1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, a significant portion of the protein is affected and the impacted region is critical for protein function (Ambry internal data). This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MLH1/PMS2 expression by immunohistochemistry (Zumstein V et al. Swiss Med Wkly, 2016 May;146:w14315; Domingo E et al. J Med Genet, 2004 Sep;41:664-8). Other alterations impacting the same donor site (c.2103+1G>A, c.2103+2T>A) have been detected in probands who met Amsterdam I/II criteria for Lynch syndrome, or probands, whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV003593881	SCV004293475	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 18 of the MLH1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with MLH1-related conditions (PMID: 15342696, 28195393, 31297992). ClinVar contains an entry for this variant (Variation ID: 90046). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Trp714*) have been determined to be pathogenic (PMID: 8863153, 9697702, 12799449, 12810663, 16338176, 17510385, 20533529). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.