7-5987077-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS1

The NM_000535.7(PMS2):c.1688G>A(p.Arg563Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,784 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R563L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: -0.0260

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 -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-5987077-C-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.013562292).

BP6

Variant 7-5987077-C-T is Benign according to our data. Variant chr7-5987077-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141394.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4}. Variant chr7-5987077-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (24/152226) while in subpopulation EAS AF= 0.00116 (6/5180). AF 95% confidence interval is 0.000504. There are 0 homozygotes in gnomad4. There are 7 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.1688G>A	p.Arg563Gln	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.1688G>A	p.Arg563Gln	missense_variant	Exon 11 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000275

AC:

AN:

251182

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000151

AC:

220

AN:

1461558

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000308

Gnomad4 EAS exome

AF:

0.00103

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000158

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lynch syndrome 4

Uncertain:3

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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jul 06, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Jun 29, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 31, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2023

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. -

not specified

Uncertain:1Benign:1

Aug 09, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.2506G>C, in exon 15 that results in an amino acid change, p.Glu836Gln. This sequence change does not appear to have been previously described in individuals with PMS2-related disorders and has also not been described in population databases such as ExAC and gnomAD. The p.Glu836Gln change affects a moderately conserved amino acid residue located in a domain of the PMS2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu836Gln substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu836Gln change remains unknown at this time. -

Dec 03, 2019

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.1688G>A (p.Arg563Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251182 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 24 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Non-Polyposis Colon Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1688G>A has been reported in the literature in individuals affected with breast cancer (Balogh_2006, Liu_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Uncertain:1Benign:1

Apr 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17016615, 29596542, 28135048, 24362816, 30093976, 28717660, 32039725, 31666926, 29212164, 35449176) -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMS2: BP4, BS2 -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Jan 22, 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

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.2

DANN

Benign

0.85

DEOGEN2

Benign

0.11

T;.;.;.;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.60

T;T;.;T;.

M_CAP

Benign

0.018

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;.;.;.;.

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.75

N;N;.;.;.

REVEL

Benign

0.18

Sift

Benign

0.63

T;T;.;.;.

Sift4G

Benign

0.57

T;T;.;.;.

Polyphen

0.023

B;B;.;.;B

Vest4

0.25

MVP

0.48

MPC

0.042

ClinPred

0.0029

GERP RS

-0.27

Varity_R

0.021

gMVP

0.18

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