7-5982823-C-T

Variant names:

• chr7-5982823-C-T
• rs267608172
• NM_000535.7:c.2174+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000535.7(PMS2):​c.2174+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,609,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PMS2 NM_000535.7 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 7.90

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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.064889915 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 7-5982823-C-T is Pathogenic according to our data. Variant chr7-5982823-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 91329.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5982823-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2174+1G>A		splice_donor_variant, intron_variant	Intron 12 of 14	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2174+1G>A		splice_donor_variant, intron_variant	Intron 12 of 14	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151638 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 244414 Hom.: 0 AF XY: 0.00000754 AC XY: 1 AN XY: 132618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000961 AC: 14 AN: 1457344 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 724940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000991

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151756 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74188

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5 Other:1

Nov 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts a canonical splice-donor site and interferes with normal PMS2 mRNA splicing. The frequency of this variant in the general population, 0.000016 (4/244414 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 28135145 (2017), 27435373 (2016), 26681312 (2015)), breast cancer (PMID: 25186627 (2015)), ovarian cancer (PMID: 20205264 (2010)), and pancreatic cancer (PMID: 30067863 (2018)). The variant has also been reported in an individual with constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 21376568 (2011)). Splicing analysis studies have shown that this variant results in aberrant splicing (PMID: 26247049 (2015), 21376568 (2011)). Based on the available information, this variant is classified as pathogenic. -

Jul 18, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to cause aberrant splicing resulting in multiple transcripts in a gene for which loss of function is a known mechanism of disease (PMID: 21376568, 26247049); Identified in the heterozygous state in patients with Lynch syndrome-related cancers (PMID: 18602922, 20205264, 28135145, 31992580, 33194656); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 18602922, 20205264, 26247049, 26681312, 28726808, 28135145, 25186627, 30067863, 31992580, 33194656, 30787465, 33087929, 38355628, 27435373, 26110232, 20533529, 23012243, 25980754, 38503638, 38344144, 37534630, 21376568) -

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MutSpliceDB: a database of splice sites variants effects on splicing, NIH

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:3

Apr 19, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2174+1G>A variant in PMS2 has been reported in 1 heterozygous individual with PMS2-associated cancers, and in 1 compound heterozygous and 1 homozygous individual with constitutional mismatch repair deficiency (Senter 2008, Herkert 2011). It segregated in a compound heterozygous state with disease in one affect sibling (Herkert 2011). It has also has been identified in 1/30070 of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that the c.2174+1G>A variant may impact the protein (Van Der Klift, 2015). In addition, it was classified as Pathogenic on April 16, 2014 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108333.3). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based. ACMG/AMP criteria applied: PM2, PS4_Supporting, PM3_Supporting, PVS1. -

May 21, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.2174+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. RNA analysis was performed to study the effect of c.2174+1G>A on mRNA splicing and to confirm that this mutation is located in PMS2 and not in its highly homologous pseudogene PMS2CL. The variant allele was found at a frequency of 1.7e-05 in 239230 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (1.7e-05 vs 0.00011), allowing no conclusion about variant significance. c.2174+1G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome and features of CMMRD. Specifically, the variant has been cited in multiple patients in both heterozygous, compound heterozygous (in trans with a second pathogenic PMS2 variant), and homozygous state, several of whom have loss of PMS2 via IHC. Carrying two MMR mutations in PMS2 in trans has been associated with constitutional mismatch repair-deficiency, which is characterized by colonic polyposis and hematologic, brain and gastrointestinal malignancies, as well as neurofribromas, which present at a young age and thus both mutations may be explaining the phenotype in the individuals reported. The variant alone was found in unaffected parents of probands, further supporting the idea that the variant is involved in constitutional mismatch repair-deficiency. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, but does not provide convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 14, 2014

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Interrupts canonical donor splice site -

Lynch syndrome 4 Pathogenic:3

Apr 05, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Jun 01, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Pathogenic:1

Mar 21, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PMS2-related disorder Pathogenic:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMS2 c.2174+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in individuals with Lynch syndrome (Senter et al. 2008. PubMed ID: 18602922; Wang et al. 2020. PubMed ID: 31992580) as well as individuals with colorectal, breast, ovarian, and pancreatic cancers (Table S1 - Susswein et al. 2015. PubMed ID: 26681312; Supporting Data - Tung et al. 2014. PubMed ID: 25186627; Brand et al. 2018. PubMed ID: 30067863). It has also been reported in the compound heterozygous and homozygous state in individuals with constitutional mismatch repair syndrome (Herkert et al. 2011. PubMed ID: 21376568). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91329/). Variants that disrupt consensus GT donor sites in PMS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1

Mar 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 12 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. Disruption of this splice site has been observed in individuals with colorectal cancer, breast cancer, ovarian cancer, pancreatic cancer, suspected Lynch syndrome, and constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20205264, 21376568, 23012243, 25186627, 26110232, 26681312, 28135145, 30067863). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 91329). Studies have shown that disruption of this splice site results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 21376568, 26247049). This variant disrupts the MLH1 interaction domain of the PMS2 protein, which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). While functional studies have not been performed to directly test the effect of this variant on PMS2 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 10, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2174+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the PMS2 gene. 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). A splicing minigene assay and RNA analysis has demonstrated aberrant splicing (van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3(4):327-45). This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated loss of PMS2 by immunohistochemistry (IHC) (Senter L et al. Gastroenterology. 2008 Aug;135(2):419-28; Yurgelun MB et al. J Clin Oncol. 2017 Apr 1;35(10):1086-1095; Brand R et al. Cancer, 2018 09;124:3520-3527; Wang Q et al. J Med Genet, 2020 07;57:487-499). This mutation has also been detected in the homozygous and compound heterozygous state in multiple patients with constitutional mismatch repair deficiency (CMMR-D) syndrome (Vaughn CP et al. Hum Mutat. 2010 May;31(5):588-93; Herkert JC et al. Eur. J. Cancer. 2011 May;47(7):965-82). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Benign	0.96
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608172; hg19: chr7-6022454; COSMIC: COSV56222103; COSMIC: COSV56222103;