Submissions for variant NM_000249.4(MLH1):c.2101C>T (p.Gln701Ter)

dbSNP: rs63750114

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075528	SCV000106525	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	RCV000075528	SCV001338532	pathogenic	Lynch syndrome	2020-04-17	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2101C>T (p.Gln701X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 250694 control chromosomes (gnomAD). c.2101C>T has been reported in the literature in individuals affected with Lynch Syndrome and colorectal cancer (Yan_2008, Kovac_2011). In addition, this variant was reported as de novo mutation in one individual affected with rectal cancer (Stulp_2006). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, one expert panel (InSiGHT) cited this variant as pathogenic on 2013. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001854297	SCV002231102	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-09-12	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 90043). This premature translational stop signal has been observed in individual(s) with rectal cancer (PMID: 16521201). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln701*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the MLH1 protein. 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	RCV002415540	SCV002728362	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-13	criteria provided, single submitter	clinical testing	The p.Q701* variant (also known as c.2101C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2101. This changes the amino acid from a glutamine to a stop codon within coding exon 18. This mutation was confirmed as a de novo germline mutation in a patient with rectal cancer at age 35 and no family history of Lynch syndrome-related cancers (Stulp RP et al. World J. Gastroenterol., 2006 Feb;12:809-11). This mutation has also been identified in a Chinese patient who was diagnosed with both endometrial and rectal cancers and whose family met Amsterdam II criteria (Yan HL et al. Cancer Sci., 2008 Apr;99:770-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003451104	SCV004186353	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.
Baylor Genetics	RCV003451104	SCV004193045	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-06-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003480053	SCV004224749	likely pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	PP4, PP5, PM2, PVS1_strong