Submissions for variant NM_000249.4(MLH1):c.38_39insCCCA (p.Glu13fs)

dbSNP: rs63750057

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075695	SCV000106681	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000479728	SCV000566197	pathogenic	not provided	2019-06-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database.; This variant is associated with the following publications: (PMID: 15571801)
Invitae	RCV001235123	SCV001407793	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu13Aspfs*19) 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 Lynch syndrome (PMID: 15571801). ClinVar contains an entry for this variant (Variation ID: 90207). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002354262	SCV002622266	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	clinical testing	The c.38_39insCCCA pathogenic mutation, located in coding exon 1 of the MLH1 gene, results from an insertion of 4 nucleotides at position 38, causing a translational frameshift with a predicted alternate stop codon (p.E13Dfs*19). This mutation was reported in a French patient with metachronous colon cancers whose family history met Amsterdam criteria (Rey JM et al. Cancer Genet Cytogenet, 2004 Dec;155:149-51). 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.	RCV003451145	SCV004189712	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357978	SCV001553594	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.Glu13Aspfsx19 variant was identified in the literature in a French patient with Lynch Syndrome based on Amsterdam criteria; the patient had 3 re-occurring colon cancers and 3 relatives with colon cancer history (Rey_2004_15571801). The variant was also identified in the following databases: dbSNP (ID: rs63750057) as “With Pathogenic allele”, ClinVar (2x, as pathogenic by InSight and GeneDx), Clinvitae (2x, as pathogenic by ClinVar), UMD-LSDB (6 records, as causal, validated by French MMR network), Insight Colon Cancer Gene Variant Database (1x, as class 5), Mismatch Repair Genes Variant Database (1x), Insight Hereditary Tumors Database (1x, as class 5). The variant was not identified in Cosmic, MutDB and Zhejiang Colon Cancer Databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.38_39insCCCA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 13 and leads to a premature stop codon 19 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch Syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.