Submissions for variant NM_000249.4(MLH1):c.1190del (p.Leu397fs)

dbSNP: rs63750749

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075145	SCV000106136	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000165649	SCV000216386	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-12	criteria provided, single submitter	clinical testing	The c.1190delT pathogenic mutation, located in coding exon 12 of the MLH1 gene, results from a deletion of one nucleotide at position 1190, causing a translational frameshift with a predicted alternate stop codon (p.L397Rfs*4). This alteration was first reported in the literature in a female diagnosed with endometrial cancer at age 52 and colon cancer at age 55 (Millar AL et al. Hum Mol Genet.1999 May;8(5):823-9). Subsequently, this alteration was identified in a male diagnosed with gastric cancer at age 35 that was MSI-High and IHC staining showed loss of MLH1; however, the patient did not have a family history of cancer (Bacani J et al. J Mol Diagn. 2005 Oct;7:465-77). This mutation was also identified in a female diagnosed with colon cancer at age 48 who met Bethesda criteria; however, her colon tumor was MSI-Low and IHC staining showed loss of MLH1, MSH2, and MSH6 (Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354:2751-63). 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.
Invitae	RCV000524227	SCV000543583	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu397Argfs*4) 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). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 10196371, 25559809). ClinVar contains an entry for this variant (Variation ID: 89673). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003451010	SCV004186389	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-19	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353740	SCV000592398	uncertain significance	not provided		no assertion criteria provided	clinical testing