Submissions for variant NM_000249.4(MLH1):c.1528C>T (p.Gln510Ter)

dbSNP: rs63749923

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075235	SCV000106228	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000699744	SCV000828469	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln510*) 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 premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 9788388, 10985134, 17087981, 20864636, 24122200). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89761). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002390219	SCV002705177	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-12	criteria provided, single submitter	clinical testing	The p.Q510* pathogenic mutation (also known as c.1528C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1528. This changes the amino acid from a glutamine to a stop codon within coding exon 13. A study of extracolonic tumors in women who carry the p.Q510X mutation showed an increase in endometrial, ovarian, renal, and breast cancers as compared to controls, however this increase was not statistically significant (Blokhuis MM et al. Fam. Cancer, 2008 Nov;7:191-8). Another study by the same group indicated that those who carry the p.Q510X mutation have a high risk of developing colon cancer (51% in this study) but do not have a significantly increased risk for extracolonic cancers (Stupart DA et al. Fam. Cancer, 2009 Aug;8:519-23). This alteration was also detected in one patient diagnosed with colorectal cancer at age 42 whose tumor had high microsatellite instability and absent MLH1 on immunohistochemistry (Perera S et al. J Mol Diagn, 2010 Nov;12:757-64). This alteration was identified in a homozygous state in an individual diagnosed with an astryocytoma at age 4 and who also had cafe au lait spots and her father, heterozygous for this alteration, was diagnosed with colon cancer at 32 (Bruwer Z et al. J Genet Couns, 2014 Apr;23:147-55). In addition to the clinical data presented in the literature, 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.	RCV003451030	SCV004186467	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-20	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.