Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000491473 | SCV000580429 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-01-06 | criteria provided, single submitter | clinical testing | The c.989dupT pathogenic mutation, located in coding exon 6 of the MSH2 gene, results from a duplication of T at nucleotide position 989, causing a translational frameshift with a predicted alternate stop codon. This alteration was previously identified in one individual who was diagnosed with endometrial cancer at age 42 and a sebaceous adenoma at age 66. This individual's mother was diagnosed with endometrial cancer at age 50 and bladder cancer at age 91 (Everett JN, JAMA Dermatol 2014 Dec; 150(12):1315-21). In addition to the clinical history presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). |
| Myriad Genetics, |
RCV003449342 | SCV004187002 | pathogenic | Lynch syndrome 1 | 2023-07-28 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Laboratory for Molecular Medicine, |
RCV004017646 | SCV004848539 | likely pathogenic | Lynch syndrome | 2021-10-28 | criteria provided, single submitter | clinical testing | The p.Asn331GlufsX2 variant in MSH2 has been reported in 1 individual with an MSH2-associated cancer (Everett 2014 PMID: 25006859). It was also reported by other clinical laboratories in ClinVar (Variation ID: 428458) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 331 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting. |