7-5999091-T-C

Position:

chr7-5999091-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000535.7(PMS2):c.705+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,611,450 control chromosomes in the GnomAD database, including 124,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.34 ( 9552 hom., cov: 31)

Exomes 𝑓: 0.39 ( 115244 hom. )

Consequence

PMS2
NM_000535.7 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:18

Conservation

PhyloP100: -0.869

Variant links:

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 links:

PMS2 (HGNC:):

PMS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 7-5999091-T-C is Benign according to our data. Variant chr7-5999091-T-C is described in ClinVar as [Benign]. Clinvar id is 36692.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5999091-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7 linkuse as main transcript	c.705+17A>G		intron_variant		ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 linkuse as main transcript	c.705+17A>G		intron_variant		1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

51785

AN:

151804

Hom.:

9544

Cov.:

show subpopulations

Gnomad AFR

AF:

0.202

Gnomad AMI

AF:

0.402

Gnomad AMR

AF:

0.350

Gnomad ASJ

AF:

0.428

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.353

Gnomad FIN

AF:

0.348

Gnomad MID

AF:

0.404

Gnomad NFE

AF:

0.413

Gnomad OTH

AF:

0.355

GnomAD3 exomes

AF:

0.368

AC:

92585

AN:

251444

Hom.:

17588

AF XY:

0.375

AC XY:

50983

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.313

Gnomad ASJ exome

AF:

0.431

Gnomad EAS exome

AF:

0.365

Gnomad SAS exome

AF:

0.355

Gnomad FIN exome

AF:

0.343

Gnomad NFE exome

AF:

0.412

Gnomad OTH exome

AF:

0.381

GnomAD4 exome

AF:

0.394

AC:

575007

AN:

1459528

Hom.:

115244

Cov.:

AF XY:

0.395

AC XY:

287147

AN XY:

726216

show subpopulations

Gnomad4 AFR exome

AF:

0.190

Gnomad4 AMR exome

AF:

0.317

Gnomad4 ASJ exome

AF:

0.433

Gnomad4 EAS exome

AF:

0.371

Gnomad4 SAS exome

AF:

0.360

Gnomad4 FIN exome

AF:

0.346

Gnomad4 NFE exome

AF:

0.408

Gnomad4 OTH exome

AF:

0.387

GnomAD4 genome

AF:

0.341

AC:

51811

AN:

151922

Hom.:

9552

Cov.:

AF XY:

0.337

AC XY:

25053

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.203

Gnomad4 AMR

AF:

0.350

Gnomad4 ASJ

AF:

0.428

Gnomad4 EAS

AF:

0.373

Gnomad4 SAS

AF:

0.354

Gnomad4 FIN

AF:

0.348

Gnomad4 NFE

AF:

0.413

Gnomad4 OTH

AF:

0.353

Alfa

AF:

0.396

Hom.:

3610

Bravo

AF:

0.335

Asia WGS

AF:

0.321

AC:

1119

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Lynch syndrome 4

Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Lynch syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Breast and/or ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 21, 2021

- -

Mismatch repair cancer syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.34

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over