rs116349687

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS1

The NM_000535.7(PMS2):c.497T>C(p.Leu166Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,611,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 8.86

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 Likely_benign. Variant got -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.1675066).

BP6

Variant 7-6002493-A-G is Benign according to our data. Variant chr7-6002493-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135944.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000801 (122/152332) while in subpopulation AFR AF= 0.00284 (118/41574). AF 95% confidence interval is 0.00242. There are 0 homozygotes in gnomad4. There are 57 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.497T>C	p.Leu166Pro	missense_variant	Exon 5 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.497T>C	p.Leu166Pro	missense_variant	Exon 5 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000220

AC:

AN:

250284

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00319

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000678

AC:

AN:

1459274

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

725946

show subpopulations

Gnomad4 AFR exome

AF:

0.00260

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.000801

AC:

122

AN:

152332

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000892

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Mar 29, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with endometrial cancer, colorectal cancer, or prostate cancer, with a colon tumor from at least one individual showing loss of MLH1 and PMS2 proteins on immunohistochemistry (Ring 2016, Yurgelun 2017, Beebe-Dimmer 2018); This variant is associated with the following publications: (PMID: 29356034, 27443514, 24113346, 28135145, 25980754) -

Aug 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Jan 31, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 15, 2020

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. -

Mar 03, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Sep 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.497T>C, in exon 5 that results in an amino acid change, p.Leu166Pro. This sequence change has been previously described in individuals with colorectal cancer, colon polyps/Lynch syndrome, endometrial cancer and prostate cancer (PMIDs: 25980754, 29356034, 28135145, 27443514). This sequence change has been described in the gnomAD database with a frequency of 0.3% in the African American subpopulation (dbSNP rs116349687). The p.Leu166Pro change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Leu166Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu166Pro change remains unknown at this time. -

Dec 09, 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.497T>C (p.Leu166Pro) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 250284 control chromosomes, predominantly at a frequency of 0.0032 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 28 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 African or African-American origin. c.497T>C has been reported in the literature in sequencing studies of individuals affected with Lynch syndrome associated cancer/colorectal polyps, endometrial cancer, and early onset prostate cancer (example, Yurgelun_2017, Ring_2016, Yurgelun_2017, Beebe-Dimmer_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6, likely benign, n=1). Based on the evidence outlined above, and no emerging evidence supporting a pathognomic outcome for this variant in its evaluations spanning four years of testing at our laboratory, the variant was re-classified as likely benign. -

PMS2-related disorder

Benign:1

Sep 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

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

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;.;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;.;D;.;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.17

T;T;T;T;T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Pathogenic

3.8

H;.;.;.;.;H

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.1

D;D;.;.;.;D

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;D;.;.;.;D

Sift4G

Pathogenic

0.0010

D;D;.;.;.;D

Polyphen

1.0

D;D;.;.;D;D

Vest4

0.98

MVP

0.98

MPC

0.32

ClinPred

0.45

GERP RS

5.4

Varity_R

0.96

gMVP

0.89

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