Submissions for variant NM_000249.4(MLH1):c.665del (p.Asn222fs)

dbSNP: rs63750385

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075797	SCV000106809	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000075797	SCV000255270	pathogenic	Lynch syndrome	2015-02-17	criteria provided, single submitter	clinical testing	This sequence change deletes 1 nucleotide from exon 8 of the MLH1 mRNA (c.665delA), causing a frameshift at codon 222. This creates a premature translational stop signal (p.Asn222Metfs*7) and is expected to result in an absent or disrupted protein product. Truncating variants in MLH1 are known to be pathogenic. This particular truncation has been reported in the literature. This variant has been reported in families affected with Lynch syndrome and Muir-Torre syndrome (PMID: 24344984, 12660027, 10733117). ClinVar contains an entry for this variant (RCV000075797). For these reasons, this variant has been classified as Pathogenic.
Invitae	RCV001390389	SCV001592108	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-01-05	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: 90307). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and Muir-Torre syndrome (PMID: 10733117, 12660027, 24344984). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn222Metfs*7) 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).
Ambry Genetics	RCV002362710	SCV002661676	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-29	criteria provided, single submitter	clinical testing	The c.665delA pathogenic mutation, located in coding exon 8 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 665, causing a translational frameshift with a predicted alternate stop codon (p.N222Mfs*7). This mutation has been reported in patients and families affected with Lynch syndrome (Sarroca C et al. Dis. Colon Rectum, 2000 Mar;43:353-60; discussion 360-2; Sarroca C et al. Cancer Genet. Cytogenet., 2003 Apr;142:13-20; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2013 Dec;11:18; Lagerstedt Robinson K et al. J. Natl. Cancer Inst., 2007 Feb;99:291-9). 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.	RCV003452756	SCV004189861	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	RCV001355343	SCV001550208	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.Asn222Metfs*7 variant was identified in 4 of 1272 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome (Dominguez-Valentin 2013, Lagerstedt-Robinson 2016). The variant also segregates with the cancer phenotype in HNPCC family (Sarroca 2002). The variant was also identified in dbSNP (ID: rs63751286) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae and InSight), and in UMD-LSDB (11x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.665del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 222 and leads to a premature stop codon at position 228. 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 MLH1 associated cancers 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.