rs587779347

chr7-5989957-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PP3_Strong PP5_Very_Strong

The NM_000535.7(PMS2):c.989-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.39

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.059868675 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.8, offset of 27, new splice context is: tgatatcaatgttactccAGata. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-5989957-T-C is Pathogenic according to our data. Variant chr7-5989957-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91386.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5989957-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.989-2A>G		splice_acceptor_variant		ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.989-2A>G		splice_acceptor_variant		1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426258 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 710354

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 16, 2022	The PMS2 c.989-2A>G variant (rs587779347) is reported in the literature in individuals and families affected with Lynch syndrome or other cancers (Bonache 2018, Borras 2013, Suerink 2016, Wang 2020). This variant is also reported in ClinVar (Variation ID: 91386), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 9, which is likely to negatively impact gene function. Furthermore, in vitro functional analyses demonstrate exon 10 skipping, which leads to an in-frame deletion but removes part of the binding domain (Bonache 2018, Borras 2013, van der Klift 2015). Based on available information, this variant is considered to be pathogenic. References: Bonache S et al. Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. J Cancer Res Clin Oncol. 2018 Dec;144(12):2495-2513. PMID: 30306255. Borras E et al. Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. J Med Genet. 2013 Aug;50(8):552-63. PMID: 23709753. Suerink M et al. The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers. Genet Med. 2016 Apr;18(4):405-9. PMID: 26110232. van der Klift HM et al. Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses. Mol Genet Genomic Med. 2015 Jul;3(4):327-45. PMID: 26247049. Wang Q et al. Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. J Med Genet. 2020 Jul;57(7):487-499. PMID: 31992580. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 24, 2023	This variant disrupts a canonical splice-acceptor site and interferes with normal PMS2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with colorectal cancer (CRC) (PMIDs: 31992580 (2020), 23709753 (2013)), breast cancer (BC) (PMID: 30306255 (2018)), endometrial cancer (PMIDs: 33693762 (2021), 31992580 (2020)), bowel cancer (PMID: 31992580 (2020)), and glioblastoma multiforme (PMID: 34308366 (2021)). Functional analysis has demonstrated that this variant causes aberrant splicing and skipping of PMS2 exon 10 (PMIDs: 26247049 (2015), 23709753 (2013)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2022	Canonical splice site variant shown in patient RNA to result in an in-frame skipping of exon 10 (Borras et al., 2013; Bonache et al., 2018), which encodes a part of the critical ATPase domain (Guarne et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); Observed as apparently homozygous in a minor with glioblastoma (Fiala et al., 2021) and as heterozygous in individuals with colorectal, endometrial, and other cancers (Borras et al., 2013; Bonache et al., 2018; Wang et al., 2020; Post et al., 2021); This variant is associated with the following publications: (PMID: 24362816, 23709753, 26247049, 26110232, 25512458, 21376568, 30306255, 33693762, 31992580, 34308366, 11574484) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 30, 2023	This variant causes an A to G nucleotide substitution at the -2 position of intron 9 of the PMS2 gene. RNA studies have shown that this variant causes the in-frame skipping of exon 10, resulting in the deletion of the C-terminal ATPase domain (PMID: 23709753, 26247049, 30306255). This variant has been detected in two Spanish families, one of which met Lynch syndrome criteria and the other did not (PMID: 23709753, 30306255) and an individual affected with mismatch repair-deficient endometrial cancer (PMID: 33693762). A different variant, c.989-1G>T, causing the same splicing defect is known to be pathogenic (ClinVar variation ID: 127802). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2021	The c.989-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 10 in the PMS2 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of PMS2 expression by immunohistochemistry (IHC) (Ambry internal data). This mutation has been reported in an individuals with Lynch syndrome-related cancers whose tumors showed microsatellite instability and/or loss of PMS2 on IHC (Borras E et al. J Med Genet. 2013 Aug;50(8):552-63; Wang Q et al. J Med Genet 2020 07;57(7):487-499). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and RNA studies have demonstrated that this alteration results in abnormal splicing (Ambry internal data; Borras E et al. J Med Genet. 2013 Aug;50(8):552-63; van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3:327-45; Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function based on identification of genomic coding exon 10 deletions in Lynch syndrome families with many probands demonstrating isolated loss of PMS2 expression in their tumors by IHC (van der Klift H et al. Genes Chromosomes Cancer. 2005 Oct;44:123-38; Senter L et al. Gastroenterology. 2008 Aug;135:419-428; Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93; Tomsic J et al. Clin. Genet. 2013 Mar;83:238-43; Brea-Fernandez AJ et al. Clin. Genet. 2014 Jun;85:583-8; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Mismatch repair cancer syndrome 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Dec 15, 2020

- -

Lynch syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Interrupts canonical donor splice site -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2022

Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 23709753, 26110232, 30306255, 31992580). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 23709753, 26247049, 30306255). ClinVar contains an entry for this variant (Variation ID: 91386). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -

Lynch syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D;D;D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.95		Position offset: -29
DS_AL_spliceai		1.0		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779347; hg19: chr7-6029588; COSMIC: COSV56223578;