Submissions for variant NM_000249.4(MLH1):c.884+4A>G

dbSNP: rs267607777

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075907	SCV000106924	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant allele results in splicing abberation leading to premature stop codon: full inactivation of variant allele
Invitae	RCV000630077	SCV000751033	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with MLH1-related conditions (PMID: 17653898, 18561205, 21239990, 25980754). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS10+4A>G. ClinVar contains an entry for this variant (Variation ID: 90414). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 10 skipping and introduces a premature termination codon (PMID: 1856120, 17653898). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the p.Arg265 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24344984, 28874130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001018387	SCV001179619	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-16	criteria provided, single submitter	clinical testing	The c.884+4A>G intronic pathogenic mutation results from an A to G substitution four nucleotides after coding exon 10 in the MLH1 gene. In one study, this variant was observed in two individuals fulfilling Bethesda criteria, whose tumors showed high microsatellite instability (MSI-H) and absence of MLH1 staining on immunohistochemistry. Furthermore, the variant was observed to segregate with colon cancer in the father and sister of one proband (Rahner N et al. Acta Oncol. 2007;46(6):763-9). This variant was also identified in an Italian proband whose tumor was MSI-H (Pastrello C et al. Genet Med, 2011 Feb;13:115-24). In silico splice site analysis for this alteration is inconclusive. Functional splicing analysis by RT-PCR using patient samples and in a mini gene assay demonstrated exon 10 skipping was associated with this variant (Rahner N et al. Acta Oncol. 2007;46(6):763-9; Tournier I et al. Hum. Mutat. 2008;29(12):1412-24; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001582561	SCV001819853	pathogenic	not provided	2023-04-03	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Rahner et al., 2007; Tournier et al., 2010); Not observed in large population cohorts (gnomAD); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Rahner et al., 2007; Barrow et al., 2010; Kim et al., 2010; Pastrello et al., 2011; Yurgelun et al., 2015; Patel et al., 2021); This variant is associated with the following publications: (PMID: 21239990, 25525159, 18561205, 21034533, 20459533, 17653898, 19339519, 24333619, 33436027, 25980754)
Myriad Genetics, Inc.	RCV003452783	SCV004188232	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205, 17653898].
Baylor Genetics	RCV003452783	SCV004193074	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-06-16	criteria provided, single submitter	clinical testing