7-5973395-ACGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTC-A

Position:

• chr7-5973395-ACGGTCAGTTCTGAGAAATGACACCCAGGTTGGCGATGTGTCTCATGGTTGGCCTTCCATGGGGACAGTTCCAGGGGTGGTCCATCTCCCCCATGTGGGTGATCAGTTTCTTCATCTCGCTTGTGTTAAGAGCAGTCCCAATCATCACCTGAGTGTGAGACACAATGGTTCAACGTTTTAGTAGTTTTTTGACGTCAGAATGGCAGCTCTTCAGAAGCATTCTTCTCTAAAATAAGGCTGGACAAGATTACAGCTCAAAAACTACCTTCCCTGAAAAACCTTCCCCCAGAGAAGCCTAGGTTCTAGATCTCAGCCCTC-A

Variant summary

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

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).

• 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 7-5973395-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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2446-170_*3del		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.2446-170_*3del		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

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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. -

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: chr7-6013026;