Submissions for variant NM_000249.4(MLH1):c.31del (p.Leu11fs)

dbSNP: rs63749816

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075653	SCV000106655	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding variation introducing premature termination codon
Invitae	RCV001045287	SCV001209128	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu11Trpfs*6) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90166). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 17203532). It has also been observed to segregate with disease in related individuals.
Ambry Genetics	RCV002321563	SCV002609139	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-14	criteria provided, single submitter	clinical testing	The c.31delC pathogenic mutation, located in coding exon 1 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 31, causing a translational frameshift with a predicted alternate stop codon (p.L11Wfs*6). This variant was reported to segregate with disease in a large Bulgarian family that met Amsterdam criteria for Lynch syndrome and several family members had colon tumors that demonstrated microsatellite instability with loss of MLH1 expression on immunohistochemistry (IHC) (Kadiyska TK et al. World J Gastroenterol, 2006 Dec;12:7848-51). This variant has also been identified in a proband who met Amsterdam criteria for Lynch syndrome and tumor demonstrated loss of both MLH1/PMS2 expression on IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451133	SCV004186496	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.