Submissions for variant NM_000249.4(MLH1):c.156del (p.Glu53fs)

dbSNP: rs63750028

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075267	SCV000106261	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000213962	SCV000276778	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-31	criteria provided, single submitter	clinical testing	The c.156delA pathogenic mutation, located in coding exon 2 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 156, causing a translational frameshift with a predicted alternate stop codon (p.E53Rfs*4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000533345	SCV000625082	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-20	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: 89793). This premature translational stop signal has been observed in individual(s) with MLH1-related conditions (PMID: 15713769, 24362816, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu53Argfs*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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075267	SCV000696118	likely pathogenic	Lynch syndrome	2017-01-19	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.156delA (p.Glu53Argfs) 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.Leu404fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121360 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001027534	SCV001161674	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2019-08-23	criteria provided, single submitter	clinical testing	The heterozygous deletion c.156delA (p.Glu53ArgfsTer4) lies in exon 2 of the MLH1 gene and is predicted to cause a frameshift and consequent premature termination of the protein. The resultant protein is likely to lack the major functional domains of the protein, this will likely result in loss of function. The variant has been reported in the ClinVar database as pathogenic. The variant has been previously reported in patients affected with Lynch Syndrome and it is indicated to be disease causing. In summary, the variant meets our criteria to be classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000213962	SCV002053145	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-28	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 2 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a family affected with Lynch syndrome (Elias 2017, doi.org/10.24870/cjb.2017-a238). Eight members of this family were identified as carriers, of which three members were affected (age of onset <30 years in one individual and >40 years in two individuals). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV001027534	SCV004186462	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075267	SCV004848600	likely pathogenic	Lynch syndrome	2021-11-16	criteria provided, single submitter	clinical testing	The p.Glu53ArgfsX4 variant in MLH1 has been reported in an individual referred for genetic testing for Lynch Syndrome (Espenschied 2017 PMID: 28514183) and was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 53 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MLH1 gene is an established disease mechanism in autosomal dominant Lynch syndrome. Moreover, this variant was also classified as pathogenic on Sep 05, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89793). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.
Mayo Clinic Laboratories, Mayo Clinic	RCV000582660	SCV000691841	likely pathogenic	not provided		no assertion criteria provided	clinical testing