rs10000

Positions:

chr7-5973522-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000535.7(PMS2):c.2466T>C(p.Leu822Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.11 ( 91 hom., cov: 9)

Exomes 𝑓: 0.13 ( 2515 hom. )

Consequence

PMS2
NM_000535.7 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:15

Conservation

PhyloP100: -0.920

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 7-5973522-A-G is Benign according to our data. Variant chr7-5973522-A-G is described in ClinVar as [Benign]. Clinvar id is 36690.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5973522-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 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.2466T>C	p.Leu822Leu	synonymous_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.2466T>C	p.Leu822Leu	synonymous_variant	15/15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.114

AC:

8266

AN:

72292

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0529

Gnomad AMI

AF:

0.198

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.0361

Gnomad SAS

AF:

0.146

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.170

Gnomad NFE

AF:

0.146

Gnomad OTH

AF:

0.139

GnomAD3 exomes

AF:

0.110

AC:

15089

AN:

136684

Hom.:

518

AF XY:

0.115

AC XY:

8408

AN XY:

72926

show subpopulations

Gnomad AFR exome

AF:

0.0471

Gnomad AMR exome

AF:

0.0587

Gnomad ASJ exome

AF:

0.138

Gnomad EAS exome

AF:

0.0381

Gnomad SAS exome

AF:

0.139

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.143

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.127

AC:

65729

AN:

515862

Hom.:

2515

Cov.:

AF XY:

0.129

AC XY:

35287

AN XY:

273858

show subpopulations

Gnomad4 AFR exome

AF:

0.0490

Gnomad4 AMR exome

AF:

0.0632

Gnomad4 ASJ exome

AF:

0.130

Gnomad4 EAS exome

AF:

0.0319

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.105

Gnomad4 NFE exome

AF:

0.146

Gnomad4 OTH exome

AF:

0.126

GnomAD4 genome

AF:

0.114

AC:

8277

AN:

72368

Hom.:

Cov.:

AF XY:

0.115

AC XY:

3829

AN XY:

33250

show subpopulations

Gnomad4 AFR

AF:

0.0530

Gnomad4 AMR

AF:

0.113

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.0366

Gnomad4 SAS

AF:

0.149

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.146

Gnomad4 OTH

AF:

0.136

Alfa

AF:

0.110

Hom.:

109

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:15

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)	Mar 04, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Lynch syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jul 01, 2016	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 49 year old male with a family history of colorectal cancer and/or polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Benign, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 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	Oct 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 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. -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Lynch syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Endometrial carcinoma

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.2466T>C, p.Leu822= variant was identified in 11% of132692 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.18

DANN

Benign

0.64

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