rs63750049

chr7-5989922-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000535.7(PMS2):c.1021del(p.Arg341GlyfsTer15) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000822 in 1,459,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R341R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 4.79

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-5989922-CT-C is Pathogenic according to our data. Variant chr7-5989922-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 9240.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5989922-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.1021del	p.Arg341GlyfsTer15	frameshift_variant	10/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.1021del	p.Arg341GlyfsTer15	frameshift_variant	10/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459050 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 725848

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: 0.00000991

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2019	The p.Arg341GlyfsX15 variant in PMS2 has been identified in at least 1 individual with PMS2-associated cancer and segregated with the disease in 2 affected family members (one with endometrial cancer and one with colon polyps; Worthley 2005). This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 341 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon predicted impact to the protein. ACMG/AMP Criteria applied: PM2, PVS1. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 28, 2020	This variant deletes 1 nucleotide in exon 10 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with colorectal cancer (PMID: 15887124, 18602922) and sebaceous neoplasms (PMID: 29333623). 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	Mar 30, 2022	The c.1021delA pathogenic mutation, located in coding exon 10 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1021, causing a translational frameshift with a predicted alternate stop codon (p.R341Gfs*15). This mutation has been reported in multiple individuals with early onset colon cancer and was found to segregate with disease in a family meeting Amsterdam II criteria (Worthley DL et al. Gastroenterology. 2005 May;128:1431-6; Senter L et al. Gastroenterology. 2008 Aug;135:419-28). This mutation was also detected in an individual with a history of prostate cancer at age 55 and colorectal cancer of the splenic flexure at 57. The authors referred to this alteration as c.1018delA (Truninger K et al. Gastroenterology. 2005 May;128:1160-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 20, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2005	- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 08, 2021

Variant summary: PMS2 c.1021delA (p.Arg341GlyfsX15) 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 was absent in 250990 control chromosomes (gnomAD). c.1021delA has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer and was shown to segregate with disease in at least 1 family (e.g. Truninger_2005, Worthley_2006, Senter_2008, Schon_2018). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2018

This deletion of one nucleotide in PMS2 is denoted c.1021delA at the cDNA level and p.Arg341GlyfsX15 (R341GfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is TAAA[delA]GGCA. The deletion causes a frameshift, which changes an Arginine to a Glycine at codon 341, and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PMS2 c.1021delA has been identified in a family meeting Amsterdam II criteria for HNPCC, and tumors from carriers of this variant have exhibited microsatellite instability and loss of PMS2 expression by immunohistochemistry (IHC) (Worthley 2005, Senter 2008). We consider this variant to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 9240). This variant is also known as c.1018delA. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15887099, 15887124, 18602922). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg341Glyfs*15) 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). -

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: rs63750049; hg19: chr7-6029553;