ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1946del (p.Pro649fs)

dbSNP: rs281864938
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075434 SCV000106430 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Labcorp Genetics (formerly Invitae), Labcorp RCV000560442 SCV000625112 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-09-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89954). This premature translational stop signal has been observed in individuals with Lynch syndrome with high tumor microsatellite instability (PMID: 10521294, 11291077, 14645426, 16116158, 19224586, 20215533). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro649Leufs*12) 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).
Ambry Genetics RCV002408589 SCV002723985 pathogenic Hereditary cancer-predisposing syndrome 2022-07-19 criteria provided, single submitter clinical testing The c.1946delC pathogenic mutation, located in coding exon 17 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 1946, causing a translational frameshift with a predicted alternate stop codon (p.P649Lfs*12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation was identified in conjunction with a MSH6 missense alteration in a proband with MSI-H endometrial cancer (Wu Y et al. Am. J. Hum. Genet. 1999 Nov;65:1291-8) and has since been reported in individuals meeting Amsterdam criteria with MSI-H tumors and/or absent MLH1 staining by IHC analysis (Berends MJ et al. J. Clin. Oncol. 2003 Dec;21:4364-70; Niessen RC et al. Gut 2006 Dec;55:1781-8; Yap HL et al. Fam. Cancer, 2009 Aug;8:85-94). Additionally, this mutation was seen in a male breast cancer patient whose breast tumor demonstrated loss of MLH1 and PMS2 protein expression by IHC (Walsh MD et al. Clin. Cancer Res. 2010 Apr;16:2214-24). Of note, this alteration is also designated as p.P649fs and Pro649fsX661 in published literature. In addition to the clinical data presented in the literature, 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. RCV003451085 SCV004186385 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-24 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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