rs63751300

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000535.7(PMS2):c.1559C>T(p.Ala520Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A520A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:9

Conservation

PhyloP100: 0.0520

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014580965).

BP6

Variant 7-5987206-G-A is Benign according to our data. Variant chr7-5987206-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185185.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=8}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000118 (18/152212) while in subpopulation AMR AF= 0.000655 (10/15274). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.1559C>T	p.Ala520Val	missense_variant	Exon 11 of 15	ENST00000265849.12	NP_000526.2	P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12 link	c.1559C>T	p.Ala520Val	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251252

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000118

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Dec 23, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.1559C>T (p.Ala520Val) variant has been reported in the published literature in affected individuals with suspected Lynch syndrome (PMID: 27601186 (2016)), however, the variant was noted to co-occur with a clearly pathogenic variant in a mismatch repair gene (PMIDs: 31433215 (2019), 26232782 (2015), and 25980754 (2015)). Additionally, a functional study showed inconclusive results regarding the variant's impact on protein function (PMID: 31433215 (2019)). The frequency of this variant in the general population, 0.00028 (10/35434 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with suspected Lynch syndrome (Yurgelun 2015, Lagerstedt-Robinson 2016, Okkels 2019); This variant is associated with the following publications: (PMID: 31433215, 27601186, 26232782, 20186688, 24362816, 17016615, 25980754, 22290698) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Sep 11, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Dec 06, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 17, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4

Uncertain:2

Jun 01, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not specified

Benign:2

Jan 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PMS2 c.1559C>T (p.Ala520Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 1613986 control chromosomes, predominantly at a frequency of 0.00042 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD v4.0.0 database is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1559C>T has been reported in the literature in individuals affected with Lynch syndrome-associated cancers or with suspected Lynch Syndrome (e.g., Yurgelun_2015, Nomura_2015, Lagerstedt-Robinson_2016, Balogh_2006, Okkels_2019, Li_2020), frequently along with PMS2 c.1556A>G (p.Y519C; Yurgelun_2015, Nomura_2015, Okkels_2019). However, the variant was found not to segregate with disease in at least one family (e.g., Okkels_2019) and was also classified as a benign/likely benign polymorphism in several publications (e.g., Okkels_2019, Li_2020, Balogh_2006). These reports are not suggestive that the variant is associated with Lynch Syndrome. Additionally, co-occurrences with other pathogenic variants have been reported (MSH2 c.2210+1G>A (Yurgelun_2015); PMS2 c.1492_1502del11 (p.Ser498GlyfsX3; Nomura_2015); MLH1 c.677+3A>G (Okkels_2019); MLH1 c.(1731+1_1732-1)_(*194_?)del, E16-19del (Okkels_2019)), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting the variant does not disrupt protein function, however no data was shown (e.g., Okkels_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 17016615, 27601186, 31391288, 26232782, 31433215, 25980754). ClinVar contains an entry for this variant (Variation ID: 185185). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 5

Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.1559C>T (p.Ala520Val) in PMS2 gene has been reported in the literature in several affected individuals (Yurgelun et.al.,2015). This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ala520Val variant is reported with allele frequency of 0.007076% in gnomAD exomes and novel in gnomAD Exomes and 1000 Genomes. The amino acid Ala at position 520 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala520Val in PMS2 is predicted as conserved by PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1

Uncertain:1

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Benign:1

May 11, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome

Benign:1

Jan 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4

Benign:1

Aug 04, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.9

DANN

Benign

0.87

DEOGEN2

Benign

0.099

T;.;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.40

T;T;.;T;.

M_CAP

Benign

0.024

MetaRNN

Benign

0.015

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.90

L;.;.;.;.

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

N;N;.;.;.

REVEL

Benign

0.090

Sift

Benign

0.27

T;T;.;.;.

Sift4G

Benign

0.29

T;T;.;.;.

Polyphen

0.0020

B;B;.;.;B

Vest4

0.064

MVP

0.21

MPC

0.036

ClinPred

0.022

GERP RS

-2.8

Varity_R

0.016

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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