Submissions for variant NM_000249.4(MLH1):c.531_532delinsAT (p.Glu178Ter)

dbSNP: rs63750903

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075744	SCV000106751	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000482203	SCV000566089	pathogenic	not provided	2015-04-02	criteria provided, single submitter	clinical testing	This combined deletion and insertion is denoted MLH1 c.531_532delGGinsAT at the cDNA level and p.Glu178Ter (E178X) at the protein level. The normal sequence, with the bases that are inserted in brackets, is ATTTT[delGG][insAT]AAGT. The combined deletion and insertion creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MLH1 c.531_532delGGinsAT has been reported in at least one individual with Lynch syndrome (Weber 1999, Yuan 2006). This variant is considered pathogenic.
Invitae	RCV003593887	SCV004293450	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-25	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 90255). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with uterine and rectal cancer (PMID: 10386556). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Glu178*) 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).