rs372297364

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS1_Supporting

The NM_001322011.2(PMS2):​c.-339C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000304 in 1,613,616 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

PMS2
NM_001322011.2 5_prime_UTR_premature_start_codon_gain

Scores

12
5
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:1

Conservation

PhyloP100: 4.36
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.862
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000118 (18/152008) while in subpopulation AMR AF= 0.000854 (13/15230). AF 95% confidence interval is 0.000504. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMS2NM_000535.7 linkc.595C>T p.Arg199Cys missense_variant Exon 6 of 15 ENST00000265849.12 NP_000526.2 P54278-1Q7Z3Q2B4DGM0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMS2ENST00000265849.12 linkc.595C>T p.Arg199Cys missense_variant Exon 6 of 15 1 NM_000535.7 ENSP00000265849.7 P54278-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152008
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000854
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000480
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251492
Hom.:
1
AF XY:
0.0000294
AC XY:
4
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461608
Hom.:
1
Cov.:
33
AF XY:
0.0000165
AC XY:
12
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000162
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152008
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74258
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.000854
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000480
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.000196
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:14Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4
Jul 31, 2018
True Health Diagnostics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 29, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Nov 13, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R199C variant (also known as c.595C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 595. The arginine at codon 199 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in 1/1260 individuals with a history of Lynch syndrome-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Nov 10, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 199 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in individuals affected with breast cancer (PMID: 25186627, 33471991). This variant has been identified in 9/282888 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. -

not provided Uncertain:3
Mar 14, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PMS2 c.595C>T (p.Arg199Cys) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 25186627 (2015), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)), and suspected Lynch syndrome (PMID: 25980754 (2015)). This variant was also observed in reportedly healthy individuals (PMID: 36243179 (2022)).The frequency of this variant in the general population, 0.00016 (5/30616 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Mar 01, 2017
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 19, 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 individuals with breast cancer or a Lynch syndrome-associated cancer and/or polyps (PMID: 33471991, 25186627, 25980754); This variant is associated with the following publications: (PMID: 29570743, 25980754, 25589618, 25186627, 29887214, 33471991, 11574484, 36243179) -

Lynch syndrome 4 Uncertain:3
Mar 02, 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. -

Sep 01, 2022
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PMS2 c.595C>T (p.Arg199Cys) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 including 1 homozygote (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Lynch syndrome Uncertain:2
May 01, 2018
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PMS2 NM_000535.5:c.595C>T has a 14.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. -

Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 199 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and in individuals affected with breast cancer (PMID: 25186627, 33471991). This variant has been identified in 9/282888 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. -

not specified Uncertain:1
Jan 06, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: PMS2 c.595C>T (p.Arg199Cys) results in a non-conservative amino acid change in 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 3.2e-05 in 251492 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. c.595C>T, has been reported in the literature in individuals affected with Lynch Syndrome (Tung_2015, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. 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: 25980754, 25186627). ClinVar contains an entry for this variant (Variation ID: 187514). Based on the evidence outlined above, the variant was classified as uncertain significance. -

PMS2-related disorder Uncertain:1
Dec 06, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PMS2 c.595C>T variant is predicted to result in the amino acid substitution p.Arg199Cys. This variant has been reported in a cohort of individuals with suspected Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754, supplemental table 2), and individuals with breast cancer (Tung et al. 2015. PubMed ID: 25186627, supplemental table; reported as chr7_6038849_G_A in supplementary tables, Breast Cancer Association et al. 2021. PubMed ID: 33471991). However, its pathogenicity was not determined with further studies (e.g. segregation, functional assays). This variant has a subpopulation frequency of up to 0.016% in the gnomAD database, including one homozygote and it is reported as likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187514/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Jan 28, 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
0.23
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.59
D;.;.;.;.;.
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D;D;.;D;.;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D
MetaSVM
Uncertain
0.48
D
MutationAssessor
Pathogenic
3.2
M;.;.;.;.;M
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-6.5
D;D;.;.;.;D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;D;.;.;.;D
Sift4G
Pathogenic
0.0
D;D;.;.;.;D
Polyphen
1.0
D;D;.;.;D;D
Vest4
0.94
MVP
0.92
MPC
0.30
ClinPred
0.93
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.81
gMVP
0.74

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.

Other links and lift over

dbSNP: rs372297364; hg19: chr7-6038849; COSMIC: COSV56224952; COSMIC: COSV56224952; API