Submissions for variant NM_000249.4(MLH1):c.727_730del (p.Asn243fs)

dbSNP: rs267607787

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075829	SCV000106842	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000220921	SCV000275735	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-02	criteria provided, single submitter	clinical testing	The c.727_730delAATG pathogenic mutation, located in coding exon 9 of the MLH1 gene, results from a deletion of 4 nucleotides at nucleotide positions 727 to 730, causing a translational frameshift with a predicted alternate stop codon (p.N243Vfs*10). This alteration has been previously reported in individuals meeting Amsterdam criteria, including a patient diagnosed at age 42 with a colorectal tumor lacking MLH1 expression and with a mother with colorectal cancer diagnosed at age 36, a cousin with colorectal cancer diagnosed at age 30, and a grandfather with pancreatic cancer diagnosed at age 62 (Wagner A et al. Am. J. Hum. Genet. 2003 May;72(5):1088-100; Losi L et al. Am. J. Gastroenterol. 2005 Oct;100(10):2280-7). Of note, this alteration is also reported as 243delAATG in the published literature. 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
Invitae	RCV000629958	SCV000750914	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 90338). This variant is also known as 243delAATG. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 12658575, 16181381, 17473388, 17505997). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn243Valfs*10) 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).
Color Diagnostics, LLC DBA Color Health	RCV000220921	SCV000905467	pathogenic	Hereditary cancer-predisposing syndrome	2020-04-28	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 9 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch Syndrome (PMID: 12658575, 16181381, 17473388, 17505997). 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.	RCV003452763	SCV004190027	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.