Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM4PP5
The NM_000535.7(PMS2):c.2446_2589del(p.Val816_Ter863del) variant causes a stop lost, conservative inframe deletion, splice region change involving the alteration of a conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V816V) has been classified as Likely benign.
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]
PMS2 Gene-Disease associations (from GenCC):
Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 57 uncertain in NM_000535.7
PM4
Stoplost variant in NM_000535.7
PP5
Variant 7-5973398-GTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCAC-G is Pathogenic according to our data. Variant chr7-5973398-GTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCAC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 434031.Status of the report is no_assertion_criteria_provided, 0 stars.
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
The p.Val816_Asn862delinsPro was not identified in the literature nor was it identified in the GeneInsight, HGMD, COSMIC, Mut, MMR, InSiGHT Colon Cancer and ClinVar databases. The p.Val816 residue is conserved in mammals and lower organisms. However, computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM)do not suggest that the variant may impact the protein. The c.2446_2589del variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing in 5 of 5 programs. In summary, based on the above information, this variant is classified as PATHOGENIC. -