Submissions for variant NM_000249.4(MLH1):c.588del (p.Lys196fs)

dbSNP: rs63751653

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075776	SCV000106785	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000570709	SCV000669516	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-18	criteria provided, single submitter	clinical testing	The c.588delA pathogenic mutation, located in coding exon 7 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 588, causing a translational frameshift with a predicted alternate stop codon (p.K196Nfs*6). In addition, this deletion of the last base pair of coding exon 7 is likely to have some effect on normal mRNA splicing. This mutation has been reported in multiple unrelated French families diagnosed with HNPCC/Lynch syndrome, and it was presumed to be disruptive to the native splice site; however, experimental evidence for abnormal splicing was not available (Parc Y et al. J. Med. Genet. 2003 Mar;40(3):208-13; Bonadona V et al. JAMA. 2011 Jun 8;305(22):2304-10). This alteration has also been reported in conjunction with a monoallelic MUTYH mutation in an individual with colorectal and prostate cancers, which both displayed lack of MLH1 and PMS2 protein expression by IHC (Rosty C et al. Fam. Cancer 2014 Dec;13(4):573-82; Win AK et al. Fam. Cancer 2015 Dec;14(4):575-83). In addition to being identified as germline in individuals meeting Amsterdam criteria, this mutation has been identified to be of somatic origin in conjunction with second MLH1 pathogenic mutations in multiple Lynch syndrome-related tumors (Sourrouille I et al. Fam. Cancer, 2013 Mar;12:27-33; Haraldsdottir S et al. Nat Commun, 2017 05;8:14755; Golubicki M et al. Cancers (Basel), 2021 Mar;13; Ambry internal data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation, aberrant splicing, or nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae	RCV001382873	SCV001581827	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-04-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90287). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 21642682, 25117503). This variant is present in population databases (rs35847123, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Lys196Asnfs*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).
Myriad Genetics, Inc.	RCV003456000	SCV004186553	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-17	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	RCV001353672	SCV000592363	uncertain significance	not provided		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249995	SCV001423896	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing