Submissions for variant NM_000249.4(MLH1):c.380+2T>A

dbSNP: rs267607742

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075680	SCV000106683	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Invitae	RCV001215653	SCV001387407	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-07-19	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 12655568). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 90192). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 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).
Ambry Genetics	RCV002354258	SCV002622268	pathogenic	Hereditary cancer-predisposing syndrome	2020-03-03	criteria provided, single submitter	clinical testing	The c.380+2T>A pathogenic mutation results from a T to A substitution 2 nucleotides after coding exon 4 in the MLH1 gene. One study identified this alteration in an individual diagnosed with colorectal cancer whose tumor showed absent MLH1 staining on immunohistochemistry analysis and high microsatellite instability. This study also documented co-segregation with disease as an affected brother and nephew of the proband were found to carry this mutation, while multiple unaffected family members did not (Bartosova Z et al. Hum Mutat. 2003 Apr;21(4):449). This alteration has also been reported in two additional individuals diagnosed with colon cancer (Alemayehu A et al 2008 Genes Chromosomes Cancer. 2008 Oct;47(10):906-14; Bujalkova M et al 2008 Clin Chem. 2008 Nov;54(11):1844-54). Based on nucleotide sequence alignment, this position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish or weaken the native splice donor site; however, direct evidence is unavailable. Based on the available evidence, c.380+2T>A is classified as a pathogenic mutation.
Myriad Genetics, Inc.	RCV003451140	SCV004185761	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-13	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.
All of Us Research Program, National Institutes of Health	RCV000075680	SCV004829735	pathogenic	Lynch syndrome	2023-08-14	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been observed in one family with Lynch syndrome (PMID:12655568, 18772310). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).