ClinVar Miner

Submissions for variant NM_001040108.2(MLH3):c.2793_2794del (p.Asn932fs)

dbSNP: rs754716792
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486748 SCV000566517 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing The c.2793_2794delGA variant in the MLH3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2793_2794delGA variant causes a frameshift starting with codon Asparagine 932, changes this amino acid to a Tryptophan residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Asn932TrpfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2793_2794delGA variant is observed in 2/111,646 (0.002%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.2793_2794delGA as a variant of uncertain significance.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755686 SCV000883099 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2018-11-21 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000755686 SCV003494185 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 7 2024-04-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn932Trpfs*13) in the MLH3 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MLH3 cause disease. This variant is present in population databases (rs754716792, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 419010). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV004023118 SCV004091184 uncertain significance not specified 2023-07-11 criteria provided, single submitter clinical testing The c.2793_2794delGA variant, located in coding exon 1 of the MLH3 gene, results from a deletion of two nucleotides at nucleotide positions 2793 to 2794, causing a translational frameshift with a predicted alternate stop codon (p.N932Wfs*13). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.

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