Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP3PP5
The NM_000535.7(PMS2):c.2446-170_*3del variant causes a splice acceptor, coding sequence, 3 prime UTR, intron change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (no stars).
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease,
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 7-5973395-ACGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTC-A is Pathogenic according to our data. Variant chr7-5973395-ACGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTC-A is described in ClinVar as [Pathogenic]. Clinvar id is 1049466.Status of the report is no_assertion_criteria_provided, 0 stars.
Department of Pathology and Laboratory Medicine, Sinai Health System
-
The PMS2 c.2276-?_2589+?del variant (chr:7 g.6013030_6017388del GRCh37) results in a deletion of exons 14-15, although the precise breakpoints of this deletion were not determined, nor were the effects of this variant on the resulting mRNA or protein product determined. The PMS2 c.2276-?_2589+?del variant was identified in 5(3 homozygous) of 146 proband chromosomes (frequency: 0.05) from individuals or families with constitutional mismatch repair deficiency or Lynch syndrome (Bakry 2014,Bodo 2015, Vaughn 2011). The variant was also identified in ClinVar (classified as pathogenic by Invitae). The variant was not identified in dbSNP database. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This alteration is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in PMS2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -