Submissions for variant NM_000249.4(MLH1):c.1011dup (p.Asn338fs)

dbSNP: rs63750677

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075073	SCV000106062	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000791451	SCV000255266	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn338Glnfs*24) 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 present in population databases (rs63750677, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 9833759, 19459153). ClinVar contains an entry for this variant (Variation ID: 89604). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000478965	SCV000565149	pathogenic	not provided	2018-04-12	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MLH1 is denoted c.1011dupC at the cDNA level and p.Asn338GlnfsX24 (N338QfsX24) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GCTC[dupC]AATT. The duplication causes a frameshift, which changes an Asparagine to a Glutamine at codon 338, and creates a premature stop codon at position 24 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MLH1 c.1011dupC, previously published as MLH1 1011insC, has been observed in at least two families meeting Amsterdam criteria for Lynch syndrome (Hutter 1998, Chong 2009). We consider this variant to be pathogenic.
Counsyl	RCV000576465	SCV000677788	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2017-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075073	SCV000917638	likely pathogenic	Lynch syndrome	2017-10-13	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1011dupC (p.Asn338GlnfsX24) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1210_1211delCT, p.Leu404fsX12; c.1219C>T, p.Gln407X; c.1381A>T, p.Lys461X). One in silico tool predicts a damaging outcome for this variant. This variant was found in multiple patients with Lynch syndrome (Bonadona_2011, Chong_2009, Hutter_1998). This variant was found in 1/246092 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Ambry Genetics	RCV001016999	SCV001178017	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-30	criteria provided, single submitter	clinical testing	The c.1011dupC pathogenic mutation, located in coding exon 11 of the MLH1 gene, results from a duplication of C at nucleotide position 1011, causing a translational frameshift with a predicted alternate stop codon (p.N338Qfs*24). This alteration was previously identified in two families fulfilling Amsterdam criteria for Lynch syndrome (Hutter P et al. Int. J. Cancer 1998 Dec;78(6):680-4; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812). 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.	RCV000576465	SCV004018189	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000576465	SCV004193073	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-07-07	criteria provided, single submitter	clinical testing