7-5973418-C-G

Position:

chr7-5973418-C-G

Variant summary

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

The NM_000535.7(PMS2):c.2570G>C(p.Gly857Ala) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.31 ( 2871 hom., cov: 13)

Exomes 𝑓: 0.29 ( 25635 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:22

Conservation

PhyloP100: 5.14

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 (MetaRNN=0.0023892224).

BP6

Variant 7-5973418-C-G is Benign according to our data. Variant chr7-5973418-C-G is described in ClinVar as [Benign]. Clinvar id is 36691.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5973418-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 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.2570G>C	p.Gly857Ala	missense_variant	15/15	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.2570G>C	p.Gly857Ala	missense_variant	15/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

29695

AN:

95704

Hom.:

2869

Cov.:

show subpopulations

Gnomad AFR

AF:

0.365

Gnomad AMI

AF:

0.428

Gnomad AMR

AF:

0.331

Gnomad ASJ

AF:

0.227

Gnomad EAS

AF:

0.390

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.263

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.279

Gnomad OTH

AF:

0.325

GnomAD3 exomes

AF:

0.286

AC:

57625

AN:

201394

Hom.:

7258

AF XY:

0.285

AC XY:

31260

AN XY:

109708

show subpopulations

Gnomad AFR exome

AF:

0.366

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.208

Gnomad EAS exome

AF:

0.371

Gnomad SAS exome

AF:

0.325

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.267

Gnomad OTH exome

AF:

0.268

GnomAD4 exome

AF:

0.287

AC:

250808

AN:

874968

Hom.:

25635

Cov.:

AF XY:

0.288

AC XY:

129536

AN XY:

450506

show subpopulations

Gnomad4 AFR exome

AF:

0.361

Gnomad4 AMR exome

AF:

0.300

Gnomad4 ASJ exome

AF:

0.214

Gnomad4 EAS exome

AF:

0.338

Gnomad4 SAS exome

AF:

0.330

Gnomad4 FIN exome

AF:

0.235

Gnomad4 NFE exome

AF:

0.282

Gnomad4 OTH exome

AF:

0.292

GnomAD4 genome

AF:

0.310

AC:

29718

AN:

95774

Hom.:

2871

Cov.:

AF XY:

0.315

AC XY:

14226

AN XY:

45122

show subpopulations

Gnomad4 AFR

AF:

0.365

Gnomad4 AMR

AF:

0.330

Gnomad4 ASJ

AF:

0.227

Gnomad4 EAS

AF:

0.390

Gnomad4 SAS

AF:

0.357

Gnomad4 FIN

AF:

0.263

Gnomad4 NFE

AF:

0.279

Gnomad4 OTH

AF:

0.329

Alfa

AF:

0.262

Hom.:

741

Bravo

AF:

0.295

ExAC

AF:

0.274

AC:

31248

ClinVar

Significance: Benign

Submissions summary: Benign:22

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 18, 2022	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Lynch syndrome 4

Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 11, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 22, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -

Lynch syndrome

Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2013	- -

Lynch syndrome 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Endometrial carcinoma

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PMS2 p.Gly857Ala variant was identified in 28% of 213820 control alleles in the Genome Aggregation Consortium (February 27, 2017). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015).â€šÃ„Ã¹ -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.075

T;.;.;.;.;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.68

T;T;.;T;.;T

MetaRNN

Benign

0.0024

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.32

N;.;.;.;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.79

N;N;.;.;.;N

REVEL

Benign

0.29

Sift

Benign

0.31

T;T;.;.;.;T

Sift4G

Benign

0.44

T;T;.;.;.;T

Polyphen

0.0

B;B;.;.;B;B

Vest4

0.070

MPC

1.9

ClinPred

0.0029

GERP RS

2.8

Varity_R

0.045

gMVP

0.46

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

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