7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C

Position:

• chr7-5973396-CGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTCCACCCTTCTGTGAAATCAGGCTCCTTGTGGCTCCTTCAAGGTGGCACCGCCTCCACTCCAGACGCCGACCACACCTGTCTCAGCAGCCACCCTGCCCTCTCACCCTGGCAGGTGCAGCAGCCTCCCAGCAGGCCTCCCTGCCCCACTGCGACCCCTCCGAGCCGCTCTCCACTCAGCAGCCAGTGATTACTTTTAAAGGGCTGTCAGGTTATTCATTCCACTTCACAGCTCTCCCCCTCACCTGAATAAAAGCCCCCGTCTGTCCCCTGA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.83

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]

ACMG classification

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
PMS2	NM_000535.7	c.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
PMS2	ENST00000265849.12	c.2446-440_*2del		splice_acceptor_variant, coding_sequence_variant, 3_prime_UTR_variant, intron_variant	15/15	1	NM_000535.7	ENSP00000265849	P3

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

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department 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

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;