Submissions for variant NM_000249.4(MLH1):c.251_255del (p.Lys84fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV003452477	SCV004188781	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587495	SCV005075831	pathogenic	Hereditary nonpolyposis colon cancer	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.251_255delAACTG (p.Lys84ThrfsX4) 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. The variant was absent in 251394 control chromosomes. c.251_255delAACTG has been reported in the literature in at least one individual with a personal and family history of colorectal cancer, with IHC staining of tumor tissue from this individual indicating a loss of MLH1 protein (e.g. Iordache_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30324682). ClinVar contains an entry for this variant (Variation ID: 2674281). Based on the evidence outlined above, the variant was classified as pathogenic.