rs370196722

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS1

The NM_000535.7(PMS2):c.2108C>T(p.Thr703Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000449 in 1,603,202 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 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

PMS2
NM_000535.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 10.0

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.34822008).

BP6

Variant 7-5982890-G-A is Benign according to our data. Variant chr7-5982890-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127773.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=10}.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000351 (51/1451658) while in subpopulation AFR AF= 0.000787 (26/33038). AF 95% confidence interval is 0.000551. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7 link	c.2108C>T	p.Thr703Met	missense_variant	Exon 12 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.2108C>T	p.Thr703Met	missense_variant	Exon 12 of 15	1	NM_000535.7	ENSP00000265849.7		P54278-1

Frequencies

GnomAD3 genomes

AF:

0.000139

AC:

AN:

151544

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000582

AC:

AN:

223266

Hom.:

AF XY:

0.0000411

AC XY:

AN XY:

121552

show subpopulations

Gnomad AFR exome

AF:

0.000863

Gnomad AMR exome

AF:

0.00

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:

0.0000102

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

0.0000351

AC:

AN:

1451658

Hom.:

Cov.:

AF XY:

0.0000388

AC XY:

AN XY:

721822

show subpopulations

Gnomad4 AFR exome

AF:

0.000787

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000199

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.000139

AC:

AN:

151544

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74004

show subpopulations

Gnomad4 AFR

AF:

0.000487

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000661

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Aug 23, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 703 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 19/254432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dec 14, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 18, 2021

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. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 4

Uncertain:3

Apr 05, 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. -

Jul 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Oct 14, 2024

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 patients with a personal history of a Lynch syndrome-associated cancer and/or polyps (PMID: 25980754, 37534630); This variant is associated with the following publications: (PMID: 31159747, 22949387, 18619468, Fukui2011[Chapter], 37534630, 25980754) -

May 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMS2 c.2108C>T (p.Thr703Met) variant has been reported in the published literature in an individual with Lynch syndrome related cancer (PMID: 25980754 (2015)) as well as an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 31159747 (2019)). The frequency of this variant in the general population, 0.0008 (17/21360 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1Benign:1

Dec 22, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change has been previously described in an individual with history of LS-associated cancer and/or colorectal polyps(PMID: 25980754). This sequence change has been described in the gnomAD database with a frequency of 0.080% in the African subpopulation (dbSNP rs370196722); however, population data in this region of PMS2 is not considered reliable due to high pseudogene homology. The p.Thr703Met change affects a moderately conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr703Met substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Thr703Met change remains unknown at this time. -

Dec 23, 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.2108C>T (p.Thr703Met) results in a non-conservative amino acid change located in the C-terminal dimerisation domain (IPR014790) 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 5.8e-05 in 223266 control chromosomes, predominantly at a frequency of 0.00086 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 7.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011). However, this observation needs to be cautiously considered since sequence alignment analysis suggests that the variant lies within a region of the gene that has high homology with the PMS2 pseudogene. c.2108C>T has been reported in the literature in individuals who underwent genetic testing for Lynch Syndrome or hereditary breast and ovarian cancer (Yurgelun_2015, Tsaousis_2019, Martin_2024, Bouras_2024, Sjursen_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. This variant has been reported in one patient who carries a pathogenic PMS2 variant but not affected with Constitutional Mismatch Repair Deficiency, suggesting the variant may be benign (Sjursen_2024). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37534630, 38566764, 39334433, 31159747, 25980754). ClinVar contains an entry for this variant (Variation ID: 127773). Based on the evidence outlined above, the variant was classified as likely benign. -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4

Uncertain:1

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

T;.;.;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;.;D;.;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.35

T;T;T;T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.5

M;.;.;.;.;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.6

D;D;.;.;.;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0060

D;D;.;.;.;D

Sift4G

Uncertain

0.0020

D;D;.;.;.;D

Polyphen

1.0

D;D;.;.;D;D

Vest4

0.68

MVP

0.88

MPC

3.3

ClinPred

0.46

GERP RS

4.7

Varity_R

0.57

gMVP

0.65

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