chr7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000535.7(PMS2):​c.2446-440_*2del 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).

Frequency

Genomes: not found (cov: 18)

Consequence

PMS2
NM_000535.7 splice_acceptor, coding_sequence, 3_prime_UTR, intron

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.83
Variant links:
Genes affected
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PP5
Variant 7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C is Pathogenic according to our data. Variant chr7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 1050527.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PMS2NM_000535.7 linkuse as main transcriptc.2446-440_*2del splice_acceptor_variant, coding_sequence_variant, 3_prime_UTR_variant, intron_variant 15/15 ENST00000265849.12 NP_000526.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PMS2ENST00000265849.12 linkuse as main transcriptc.2446-440_*2del splice_acceptor_variant, coding_sequence_variant, 3_prime_UTR_variant, intron_variant 15/151 NM_000535.7 ENSP00000265849 P3P54278-1

Frequencies

GnomAD3 genomes
Cov.:
18
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
18

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The PMS2 c.2007-?_2589+?del variant (chr:7 g.6013030_6022622del GRCh37) results in a deletion of exons 12 to 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.2007-?_2589+?del variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, Clinvitae, GeneInsight-COGR, Cosmic, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.2007-?_2589+?del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 670 and leads to a premature stop codon 7 codons downstream. This alteration is then 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 Lynch syndrome and this is the type of variant expected to cause the disorder. Vaughn et al 2011 identified PMS2 exon 13-15 deletion in 2 patients with colon cancer from different families. More over multiple pathogenic nonsense and frameshift variants are reported in ClinVar downstream of the p.Lys670ArgfsX7 variant. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-6013027; API