rs876659480

Positions:

• chr7-5982843-G-A
• chr7-5982843-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000535.7(PMS2):​c.2155C>T​(p.Gln719Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q719Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.57

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-5982843-G-A is Pathogenic according to our data. Variant chr7-5982843-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 231993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5982843-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2155C>T	p.Gln719Ter	stop_gained	12/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2155C>T	p.Gln719Ter	stop_gained	12/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000845 AC: 2 AN: 236580 Hom.: 0 AF XY: 0.0000156 AC XY: 2 AN XY: 128580

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1457298 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724896

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 23, 2017	The PMS2 c.2155C>T;p.Gln719Ter variant has been described in at least one family with a clinical diagnosis of Lynch syndrome (ten Broeke 2015). The variant is listed in the ClinVar database (Variation ID: 231993), but is not listed in the dbSNP variant database. The variant is listed in the Genome Aggregation Database with an allele frequency of 0.0008622 percent (2/231974 alleles). This variant introduces a premature termination codon and is predicted to result in a truncated or absent protein. Considering available information, this variant is classified as pathogenic. References: ten Broeke SW et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2015 Feb 1;33(4):319-25. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2018	This pathogenic variant is denoted PMS2 c.2155C>T at the cDNA level and p.Gln719Ter (Q719X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in families with Lynch syndrome and in one individual with colorectal cancer displaying microsatellite instability and absence of PMS2 protein via immunohistochemistry (IHC) (Guerts-Giele 2014, Suerink 2015, ten Broeke 2015). We consider this variant to be pathogenic. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 16, 2019

Variant summary: PMS2 c.2155C>T (p.Gln719X) 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 (NMD), which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.6e-06 in 231974 control chromosomes (gnomAD). c.2155C>T has been reported in the literature in individuals affected with Lynch Syndrome (Suerink 2015, ten Broeke 2015, van der Klift 2016), where in two patients the associated tumors lacked the PMS2 protein and displayed microsatellite instability (van der Klift 2016). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence, demonstrating the lack of mRNA, probably due to NMD (Suerink 2015, van der Klift 2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 231993). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome and/or prostate cancer (PMID: 25512458, 31948886). 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. This sequence change creates a premature translational stop signal (p.Gln719*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2022

The p.Q719* pathogenic mutation (also known as c.2155C>T), located in coding exon 12 of the PMS2 gene, results from a C to T substitution at nucleotide position 2155. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation was reported in one family from a cohort of 98 PMS2 positive families (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb; 33(4):319-25). This mutation was also reported in two Dutch probands diagnosed at ages 44 and 57 with MSI-H colorectal cancer and both tumors demonstrated loss of PMS2 expression by immunohistochemistry (van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179). In a cohort of European PMS2 mutation carriers, this variant was identified in three carriers (3/381) from two different families (2/130) (Suerink M et al. Genet Med, 2016 Apr;18:405-9). This mutation was also reported as homozygous in a 19 year old male proband diagnosed with colorectal cancer and leukemia in addition to having a family history of cancer (Arslan Ates E et al. Medeni Med J, 2022 Jun;37:150-158). In addition to the clinical data presented in the literature, 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. -

Lynch syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 21, 2023

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;D
Vest4		0.95
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876659480; hg19: chr7-6022474;