Submissions for variant NM_000249.4(MLH1):c.258del (p.Gln86fs)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593629	SCV004310429	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln86Hisfs*6) 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 variant has not been reported in the literature in individuals affected with MLH1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004369363	SCV004930975	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004999969	SCV005623577	likely pathogenic	not provided	2024-06-24	criteria provided, single submitter	clinical testing	The MLH1 c.258del (p.Gln86Hisfs*6) variant alters the translational reading frame of the MLH1 mRNA and is predicted to cause the premature termination of MLH1 protein synthesis. This variant has not been reported in individuals with MLH1-related conditions in the published literature. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.