ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.673dup (p.Ser225fs)

dbSNP: rs1575469505
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001025597 SCV001187818 pathogenic Hereditary cancer-predisposing syndrome 2019-02-19 criteria provided, single submitter clinical testing The c.673dupA pathogenic mutation, located in coding exon 8 of the MLH1 gene, results from a duplication of A at nucleotide position 673, causing a translational frameshift with a predicted alternate stop codon (p.S225Kfs*10). This mutation has been reported in one British HNPCC family (Taylor CF et al. Hum Mutat. 2003 Dec;22(6):428-33). 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. This nucleotide position is highly conserved in available vertebrate species.
Mayo Clinic Laboratories, Mayo Clinic RCV001507619 SCV001713274 likely pathogenic not provided 2020-11-23 criteria provided, single submitter clinical testing PVS1, PM2
Invitae RCV001862335 SCV002143439 pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser225Lysfs*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: 14635101). ClinVar contains an entry for this variant (Variation ID: 826590). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV003455133 SCV004189862 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-17 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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