rs587779335

chr7-5978683-TGA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PP5_Strong

The NM_000535.7(PMS2):c.2186_2187del(p.Leu729GlnfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. L729L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0078 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (31 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Uncertain significance reviewed by expert panel P:9 U:5 B:1
• Conservation: PhyloP100: 8.73

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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-5978683-TGA-T is Pathogenic according to our data. Variant chr7-5978683-TGA-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 91330.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Benign=1, Pathogenic=4, Likely_pathogenic=3, Uncertain_significance=5}. Variant chr7-5978683-TGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2186_2187del	p.Leu729GlnfsTer6	frameshift_variant	13/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2186_2187del	p.Leu729GlnfsTer6	frameshift_variant	13/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1150 AN: 148120 Hom.: 14 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00339

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00391

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000975 AC: 1403 AN: 1438956 Hom.: 31 AF XY: 0.000878 AC XY: 629 AN XY: 716384

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.00220

Gnomad4 ASJ exome AF: 0.000270

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000585

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00780 AC: 1156 AN: 148220 Hom.: 16 Cov.: 32 AF XY: 0.00736 AC XY: 533 AN XY: 72402

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.00339

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000148

Gnomad4 OTH AF: 0.00387

Alfa AF: 0.00567 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:9 Uncertain:5 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 4 Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 22, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 22, 2018	The PMS2 c.2186_2187delTC (p.Leu729GlnfsTer6) variant results in a frameshift and is predicted to result in the premature termination of the protein. The p.Leu729GlnfsTer6 variant has been reported in three studies in which it has been identified in five individuals from three families, including in a homozygous state in one individual with familial prostate cancer and in a compound heterozygous state in four individuals with constitutional mismatch repair deficiency (De Vos et al. 2004; Bakry et al. 2014; Leongamornlert et al. 2014). Control data are unavailable for this variant which is reported at a frequency of 0.02565 in the African population of the Genome Aggregation Database but due to possible pseudogene interference the frequency data is not reliable. Based on the clinical evidence and the potential impact of frameshift variants, the p.Leu729GlnfsTer6 variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

PMS2-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The PMS2 c.2186_2187delTC variant is predicted to result in a frameshift and premature protein termination (p.Leu729Glnfs*6). This variant (also known as 2184delTC) has been reported in 13 patients with a personal or family history of breast or ovarian cancer (Supplemental File 1, Lerner-Ellis et al. 2020. PubMed ID: 32885271). This variant has been reported in the compound heterozygous state in two siblings with Turcot syndrome (De Vos et al. 2004. PubMed ID: 15077197) and an individual with constitutional mismatch repair deficiency (Patient MMR50, Bakry et al. 2014. PubMed ID: 24440087). It has also been reported in the homozygous state in an individual with a personal and family history of prostate cancer (Patient Prs14, Leongamornlert et al. 2014. PubMed ID: 24556621). This variant is reported in 2.5% of alleles in individuals of African descent in gnomAD. This variant falls within a highly paralogous region and allele frequency data should be interpreted with caution. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/91330). Frameshift variants in PMS2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Mismatch repair cancer syndrome 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2004

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 10, 2022

Variant summary: PMS2 c.2186_2187delTC (p.Leu729GlnfsX6, also reported in the literature with legacy name c.2184delTC) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.0019 in 235662 control chromosomes in the gnomAD database, including 4 homozygotes, however this frequency data may not be reliable for this region of PMS2 known to have significant sequence overlap with pseudogenes, and it is not known whether pseudogene amplification was ruled out in these samples. This variant has been frequently identified as a non-reportable variant originating in the PMS2 pseudogene in specimens with bonafide pathogenic variation in other genes among patients undergoing multigene panel testing at our laboratory. Therefore, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2186_2187delTC has been reported in the literature in compound heterozygosity with another PMS2 variant in a family with two siblings affected with Turcot Syndrome (c.400C>T, p.R134*, e.g. DeVos_2004; patients originally described by Hamilton et al, 1995 and subsequently cited in multiple publications) and Constitutional Mismatch Repair Deficiencies (CMMRD) (c.134A>C, p.Asn45Thr, e.g. Bakry_2014). The authors report pseudogene amplification as having been ruled out in these studies. These data indicate that the variant was likely to be associated with disease in these individuals. The variant has also been reported in individuals with other cancer types, including breast (e.g. Eliade_2017, Gardner_2018) and prostate (Leongamornlert_2014), although no co-segregation evidence was reported, and in at least some of these cases, it is not clear whether pseudogene interference was ruled out. At least two publications report experimental evidence that a lymphoblastoid cell line and/or tumor tissue from a compound heterozygous patient with bi-allelic PMS2 mutations, including this one, had nearly null expression of PMS2 by IHC, however the contributions of the individual variants to these findings cannot be determined based upon this data alone (e.g. Turnbull_2012, Bakry_2014). Multiple clinical diagnostic laboratories and one expert panel (InSight) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (Uncertain significance, n=4 to include the expert panel; Pathogenic/Likely Pathogenic, n=3). Some submitters cite overlapping evidence cited in the context of our evaluation. Based on the evidence outlined above, this variant was classified as pathogenic within settings of unequivocal confirmation of its origin within the PMS2 gene. -

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Pathway Genomics

Oct 30, 2014

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2019

This sequence change creates a premature translational stop signal (p.Leu729Glnfs*6) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in several individuals affected prostate cancer and constitutional mismatch repair deficiency syndrome (PMID: 24556621, 15077197). This variant is also known as c.2184delTC in the literature. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2022

The c.2186_2187delTC pathogenic mutation, located in coding exon 13 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 2186 to 2187, causing a translational frameshift with a predicted alternate stop codon (p.L729Qfs*6). Two individuals whose clinical histories were consistent with CMMRD were found to be compound heterozygotes for this and another PMS2 mutation (Bakry D et al. Eur. J. Cancer 2014 Mar; 50(5):987-96). This pathogenic mutation has also been detected in the PMS2 pseudogene region in multiple individuals (De Vos M et al. Am. J. Hum. Genet. 2004 May;74(5):954-64; Leongamornlert D et al. Br. J. Cancer 2014 Mar;110(6):1663-72). This alteration has been classified as an uncertain variant using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies. The uncertain variant classification by the insight group is noted to be due to the possibility that this variant is located in the PMS2CL pseudogene (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation when not in the pseudogene. -

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS2 p.Leu729GlnfsX6 variant was identified in 1 of 382 proband chromosomes (frequency: 0.003) from British individuals or families with prostate cancer (Leongamornlert 2014). The variant was also identified in children affected with CMMRD (constitutional mismatch repair deficiency syndrome), co-occurring with a pathogenic PMS2 variant (R134X) in 3 studies (Bonthron 2005, Bakry 2014, De Vos 2004). The variant was identified in dbSNP (ID: rs587779335) “With Pathogenic allele”, ClinVar (uncertain significance, reviewed by an expert panel (2015); submitters: uncertain significance by InSIGHT, likely pathogenic by Pathway Genomics, likely benign by Illumina Clinical Services and pathogenic by OMIM), Clinvitae (3X), Insight Colon Cancer Gene Variant Database (Class 5), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (1x class 5), and was not identified in GeneInsight – COGR (unavailable), Cosmic, MutDB, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 419 (4 homozygous) of 231598 chromosomes at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 349 (4 homozygous) of 13606 chromosomes (frequency: 0.03), Other in 8 of 5246 chromosomes (frequency: 0.002), Latino in 42 of 32934 chromosomes (frequency: 0.001), European Non-Finnish in 16 of 102684 chromosomes (frequency: 0.0002), Ashkenazi Jewish in 3 of 9570 chromosomes (frequency: 0.0003), South Asian in 1 of 29508 chromosomes (frequency: 0.00003). The c.2186_2187del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 729 and leads to a premature stop codon 6 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 in Lynch syndrome and this 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 09, 2023

- -

Lynch syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

This variant is likely to come from pseudogene -

Mismatch repair cancer syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 22, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

PMS2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779335; hg19: chr7-6018314;