Submissions for variant NM_000249.4(MLH1):c.392C>A (p.Ser131Ter)

dbSNP: rs63749818

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075696	SCV000106700	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Neuberg Centre For Genomic Medicine, NCGM	RCV003388572	SCV004100571	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2		criteria provided, single submitter	clinical testing	The stop gained p.S131* in MLH1 (NM_000249.4) has been reported to ClinVar as Pathogenic, however details are not available for independent assessment. A different pathogenic variant having c.392C>G affecting the same p.Ser131Ter has been reported in at least four families meeting testing and/or clinical criteria for Lynch syndrome (Kurzawski 2006, Hiljadnikova-Bajro 2012) and is submitted as Pathogenic to ClinVar. The p.S131* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. The p.S131* variant is a loss of function variant in the gene MLH1, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003388572	SCV004186468	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-13	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.