Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000228583 | SCV000284083 | pathogenic | Lynch syndrome | 2016-03-04 | criteria provided, single submitter | clinical testing | This sequence change inserts 2 nucleotides in exon 11 of the MLH1 mRNA (c.961_962dupAG), causing a frameshift at codon 321. This creates a premature translational stop signal (p.Ser321Argfs*47) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816 ). For these reasons, this variant has been classified as Pathogenic. |
Invitae | RCV001389785 | SCV001591262 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-06-01 | 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: 237352). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 26248088). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser321Argfs*47) 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 | RCV002378968 | SCV002695714 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-02-08 | criteria provided, single submitter | clinical testing | The c.961_962dupAG pathogenic mutation, located in coding exon 11 of the MLH1 gene, results from a duplication of AG at nucleotide position 961, causing a translational frameshift with a predicted alternate stop codon (p.S321Rfs*47). This alteration (designated as c.962insAG) was reported in one African-American family who met Amsterdam II criteria (Guindalini RS et al. Gastroenterology, 2015 Nov;149:1446-53). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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, |
RCV003454698 | SCV004186341 | 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. |