7-5987525-CTTT-CTTTT

Position:

• chr7-5987525-CTTT-CTTTT

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.1239_1240insA​(p.Asp414ArgfsTer44) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 0.163

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 7-5987525-C-CT is Pathogenic according to our data. Variant chr7-5987525-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 216072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.1239_1240insA	p.Asp414ArgfsTer44	frameshift_variant	11/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.1239_1240insA	p.Asp414ArgfsTer44	frameshift_variant	11/15	1	NM_000535.7	ENSP00000265849	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000479 AC: 7 AN: 1461794 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PMS2: PVS1, PM2, PS4:Moderate -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2018	This duplication of one nucleotide in PMS2 is denoted c.1239dupA at the cDNA level and p.Asp414ArgfsX44 (D414RfsX44) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAAAAAA[dupA]GACG. The duplication causes a frameshift which changes an Aspartic Acid to an Arginine at codon 414, and creates a premature stop codon at position 44 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.1239dupA has been observed in the compound heterozygous state with a nonsense variant in an individual with brain cancer and duodenal cancer diagnosed prior to age 18, consistent with autosomal recessive constitutional mismatch repair deficiency syndrome (Vaughn 2010). This variant was also observed in an individual with early-onset colon cancer and family history meeting Amsterdam Criteria I (Carneiro da Silva 2015). We consider this variant to be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 22, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant consists of 1 nucleotide insertion in exon 11 of the PMS2 mRNA (c.1239dupA), causing a frameshift at codon 414. Consequently, a premature stop codon is created 44 amino acid residues later. This is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic. This variant has been described in the international literature (PMID: 26437257, PMID: 20205264). The mutation database ClinVar contains entries for this variant (Variation ID: 216072/). -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2023	This variant inserts 1 nucleotide in exon 11 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of Lynch syndrome (PMID: 26437257). This variant has also been reported in individuals affected with or suspected of constitutional mismatch repair syndrome (PMID: 20205264, 21261604, 25691505). This variant has been identified in 1/31348 chromosomes 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	Aug 19, 2021	The c.1239dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1239, causing a translational frameshift with a predicted alternate stop codon (p.D414Rfs*44). This alteration was detected in conjunction with PMS2 c.1927C>T (p.Gln643X) in a patient diagnosed with a brain tumor at age 14 and a PMS2-deficient duodenal tumor at age 15, which is consistent with a diagnosis of constitutional mismatch repair deficiency syndrome; further, this patient's mother's testing detected the c.1239dupA alteration only (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93). In a study of Brazilian patients suspected to have Lynch syndrome, this alteration was reported in a patient with colon cancer at age 37, whose family history met Amsterdam I Criteria (Carneiro da Silva F et al. PLoS ONE. 2015 Oct;10:e0139753). 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, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 20, 2022	- -

PMS2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2024

The PMS2 c.1239dupA variant is predicted to result in a frameshift and premature protein termination (p.Asp414Argfs*44). This variant has been previously reported in individuals with non-polyposis colorectal cancer/Lynch syndrome (Carneiro da Silva et al. 2015. PubMed ID: 26437257; Rossi et al. 2017. PubMed ID: 28874130; Table S2-Tsaousis et al. 2019. PubMed ID: 31159747; Vaughn et al. 2010. PubMed ID: 20205264). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD. Frameshift variants in PMS2 are expected to be pathogenic. This variant is interpreted as 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 05, 2024

Variant summary: PMS2 c.1239dupA (p.Asp414ArgfsX44) 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. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1239dupA has been reported in the literature in individuals affected with suspected Lynch Syndrome (e.g., Carneiro da Silva_2015). The following publication was ascertained in the context of this evaluation (PMID: 26437257). ClinVar contains an entry for this variant (Variation ID: 216072). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 26, 2023

This variant inserts 1 nucleotide in exon 11 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 26437257). This variant has been reported in individuals affected or suspected of having constitutional mismatch repair syndrome (PMID: 20205264, 21261604, 25691505)This variant has been identified in 1/31348 chromosomes 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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This sequence change creates a premature translational stop signal (p.Asp414Argfs*44) 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). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency-associated tumors (PMID: 20205264, 25691505, 26437257). ClinVar contains an entry for this variant (Variation ID: 216072). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs267608159; hg19: chr7-6027156;