Submissions for variant NM_000249.4(MLH1):c.1989+5G>C

dbSNP: rs267607878

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075459	SCV000887327	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.1989+5G>C has a 99.7% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Invitae	RCV001040247	SCV001203809	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-01-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Pro654Leu) have been determined to be pathogenic (PMID: 16083711, 17510385, 20533529, 21404117). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 skipping of exon 17, but is expected to preserve the integrity of the reading-frame (PMID: 8993976; Invitae). ClinVar contains an entry for this variant (Variation ID: 89977). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8993976, 14970868; Invitae). 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 falls in intron 17 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 likely results in a shortened protein product.
Ambry Genetics	RCV002415527	SCV002718426	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	clinical testing	The c.1989+5G>C intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 17 in the MLH1 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (IHC) (Ambry internal data). In addition, this alteration has been identified as somatic in conjunction with a somatic pathogenic MLH1 variant in a MSI-H colon tumor with loss of MLH1 and PMS2 expression by IHC where MLH1 promotor hypermethylation was negative (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Additionally, patient RNA demonstrated a deletion of exon 17 by RT-PCR (Viel A et al. Genes Chromosomes Cancer, 1997 Jan;18:8-18; Viel A et al. Community Genet, 1998;1:229-36; Ponz de Leon M et al. Br. J. Cancer, 2004 Feb;90:882-7; de Leon MP et al. Scand. J. Gastroenterol., 2007 Jun;42:746-53; Pedroni M et al. Dis. Markers, 2007;23:179-87). The resulting transcript is in-frame and is not expected to trigger nonsense-mediated mRNAdecay. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (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.
Myriad Genetics, Inc.	RCV003451091	SCV004187390	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8993976].