7-5997426-GAAAA-GAAA

Position:

• chr7-5997426-GAAAA-GAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.706-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (12592 hom., cov: 0)
  • Exomes 𝑓: 0.40 (4732 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:18
• Conservation: PhyloP100: 0.187

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]

PMS2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-5997426-GA-G is Benign according to our data. Variant chr7-5997426-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 218461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5997426-GA-G is described in Lovd as [Benign]. Variant chr7-5997426-GA-G is described in Lovd as [Benign]. Variant chr7-5997426-GA-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.706-4delT		splice_region_variant, intron_variant		ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.706-4delT		splice_region_variant, intron_variant		1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.447 AC: 59543 AN: 133062 Hom.: 12589 Cov.: 0

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.456

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.517

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.453

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.400 AC: 377828 AN: 944554 Hom.: 4732 Cov.: 0 AF XY: 0.403 AC XY: 194409 AN XY: 482870

Gnomad4 AFR exome AF: 0.348

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.436

Gnomad4 EAS exome AF: 0.475

Gnomad4 SAS exome AF: 0.426

Gnomad4 FIN exome AF: 0.414

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.448 AC: 59567 AN: 133100 Hom.: 12592 Cov.: 0 AF XY: 0.449 AC XY: 28627 AN XY: 63714

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.705

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.475

Gnomad4 OTH AF: 0.455

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 4 Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	GnomAD population frequency 44% -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Lynch syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 17, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2017	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 18, 2017	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 02, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Ovarian neoplasm Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

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: rs60794673; hg19: chr7-6037057;