Submissions for variant NM_000249.4(MLH1):c.347del (p.Thr116fs)

dbSNP: rs876661159

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223327	SCV000279683	pathogenic	not provided	2015-12-14	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MLH1 is denoted c.347delC at the cDNA level and p.Thr116LysfsX20(T116KfsX20) at the protein level. The normal sequence, with the base that is deleted in braces, is ATTA[C]AACG. The deletion causes a frameshift, which changes a Threonine to a Lysine at codon 116, and creates a premature stop codon at position 20 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587441	SCV000696162	likely pathogenic	Lynch syndrome	2017-04-12	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.347delC (p.Thr116Lysfs) 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. c.1210_1211delCT, p.Leu404fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121410 control chromosomes. In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae	RCV002516198	SCV003198915	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Thr116Lysfs*20) 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 variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 234680).