Submissions for variant NM_000249.4(MLH1):c.1275dup (p.Gln426fs)

dbSNP: rs2125884574

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV003449994	SCV004189789	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-19	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355250	SCV001550079	pathogenic	not provided		no assertion criteria provided	clinical testing	The MLH1 p.Gln426Alafs*4 variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant databases, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified in Insight Hereditary Tumors Database (1x). The c.1275dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 426 and leads to a premature stop codon at position 429. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant is classified as likely pathogenic.