Submissions for variant NM_000249.4(MLH1):c.860del (p.Asn287fs)

dbSNP: rs63750034

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075891	SCV000106907	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075891	SCV000917652	likely pathogenic	Lynch syndrome	2018-06-05	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.860delA (p.Asn287ThrfsX10) 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. Truncations downstream of this position have been classified as likely pathogenic/pathogenic by our laboratory (eg. c.927dupC, 1210_1211delCT and c.1489dupC). The variant was absent in 246256 control chromosomes. To our knowledge, no occurrence of c.860delA in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, but two locus specific databases cite the variant as "causative". Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243696	SCV002512767	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-07-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate
Ambry Genetics	RCV002444535	SCV002679958	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-07	criteria provided, single submitter	clinical testing	The c.860delA pathogenic mutation, located in coding exon 10 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 860, causing a translational frameshift with a predicted alternate stop codon (p.N287Tfs*10). 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.	RCV002243696	SCV004186322	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Invitae	RCV003764750	SCV004629480	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn287Thrfs*10) 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 Lynch syndrome (PMID: 31491536). ClinVar contains an entry for this variant (Variation ID: 90398). For these reasons, this variant has been classified as Pathogenic.