Submissions for variant NM_000249.4(MLH1):c.380+1G>A

dbSNP: rs267607745

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075679	SCV000106682	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000524296	SCV000284061	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-21	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 90191). Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 12655568, 15849733, 19072991). It has also been observed to segregate with disease in related individuals. 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).
GeneDx	RCV000486012	SCV000567567	pathogenic	not provided	2016-10-21	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.380+1G>A or IVS4+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 4 of the MLH1 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also published as MLH1 c.381G>A, has been reported in several individuals/families suspected to have Lynch syndrome (Scott 2001, Mangold 2005a, Mangold 2005b, Schofield 2009). Based on the current evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV001021188	SCV001182769	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-13	criteria provided, single submitter	clinical testing	The c.380+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the MLH1 gene. This variant has been reported in multiple individuals with a personal and/or family history consistent with Lynch syndrome (Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702; Mangold E et al. J. Pathol. 2005 Dec;207:385-95; Schofield L et al. Int. J. Cancer. 2009 Mar;124:1097-102; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000486012	SCV002009362	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003451139	SCV004188498	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353869	SCV000592356	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The c.380+1G>A variant has been identified in 1 out of 3546 proband chromosomes (frequency 0.014) in individuals with hereditary nonpolyposis colorectal cancer (HNPCC): however no normal population controls were included in this study (Mangold 2005). This variant located in the 5’ splice region is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant +1 and +2 positions region of the splice consensus sequence. In summary, based on the above information, this variant is classified as pathogenic.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249909	SCV001423926	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing