Submissions for variant NM_000249.4(MLH1):c.2224C>T (p.Gln742Ter)

dbSNP: rs587778992

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075580	SCV000106578	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon within functional domain in last exon
Ambry Genetics	RCV000574085	SCV000664836	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	The p.Q742* pathogenic mutation (also known as c.2224C>T), located in coding exon 19 of the MLH1 gene, results from a C to T substitution at nucleotide position 2224. This changes the amino acid from a glutamine to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 15 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function based on an internal structural analysis which suggests that this variant perturbs a known functional domain responsible for binding to as well as stabilizing PMS2 and removes a terminal cysteine residue shown to be involved in metal binding as part of a functional domain in PMS2 (Ambry internal data; Mohd AB et al. DNA Repair (Amst.) 2006 Mar;5(3):347-61; Smith CE et al. PLoS Genet. 2013 Oct;9:e1003869). This mutation has been reported in a family who met either Amsterdam or Bethesda criteria (Valentin et al. Fam Cancer. 2011 Dec;10(4):641-7), as well as in an individual with endometrial cancer at age 50 whose tumor demonstrated loss of MLH1 and PMS2 staining by immunohistochemistry (IHC) (Adar T et al. Cancer, 2018 08;124:3145-3153). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000075580	SCV000914327	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Invitae	RCV001040530	SCV001204110	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-05-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the highly conserved C-terminal domain responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). A different truncating variant downstream of this variant (p.Lys751Serfs*3) has been reported in individuals affected with Lynch syndrome and has been determined to be pathogenic (PMID: 24802709, 8797773, 27295708, 18566915, 18931482). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in an individual affected with colon cancer (PMID: 21681552). ClinVar contains an entry for this variant (Variation ID: 90094). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MLH1 gene (p.Gln742*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acids of the MLH1 protein.
Myriad Genetics, Inc.	RCV003451117	SCV004186358	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.