ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3365_3366insTT (p.Gln1122fs)

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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 RCV002454787 SCV002615464 pathogenic Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing The c.3365_3366insTT pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from an insertion of two nucleotides at position 3365, causing a translational frameshift with a predicted alternate stop codon (p.Q1122Hfs*24). 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. RCV003454112 SCV004187289 pathogenic Lynch syndrome 5 2023-08-22 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV003464451 SCV004198128 likely pathogenic Endometrial carcinoma 2022-10-05 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004005624 SCV004842702 likely pathogenic Lynch syndrome 2024-01-22 criteria provided, single submitter clinical testing The c.3365_3366insTT (p.Gln1122Hisfs*24) variant in the MSH6 gene, that encodes for mutS homolog 6, introduces a premature translation termination codon in exon 5, resulting in an absent or disrupted protein product. Loss-of-function variants in MSH6 are well known to be pathogenic and ClinGen score shows sufficient evidence of haploinsufficiency of this gene (PMID: 9354786, 11709755, 20028993, 25318681). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 18301448, 28514183, 28528517) and by several ClinVar submitters (ClinVar ID: 89377, 141166). This variant is found to be absent in the general population database, gnomAD and interpreted as pathogenic by a ClinVar submitter (ClinVar ID: 1730649). Therefore, the c.3365_3366insTT (p.Gln1122Hisfs*24) variant in the MSH6 gene is classified as likely pathogenic.

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