Submissions for variant NM_000249.4(MLH1):c.2084C>A (p.Ser695Ter)

dbSNP: rs63749995

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075523	SCV000106519	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075523	SCV000696144	likely pathogenic	Lynch syndrome	2016-10-27	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.2084C>A (p.Ser695X) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.: p.Trp714X, p.His727fsX55). Mutation taster predicts a damaging outcome for this variant. This variant is absent in 120582 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae	RCV001059462	SCV001224086	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser695*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the MLH1 protein. 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: 17505997). ClinVar contains an entry for this variant (Variation ID: 90038). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002415537	SCV002727802	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-11	criteria provided, single submitter	clinical testing	The p.S695* pathogenic mutation (also known as c.2084C>A), located in coding exon 18 of the MLH1 gene, results from a C to A substitution at nucleotide position 2084. This changes the amino acid from a serine to a stop codon within coding exon 18. 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.	RCV003455995	SCV004186435	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	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.