chr7-5999203-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000535.7(PMS2):​c.610A>C​(p.Asn204His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N204D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PMS2
NM_000535.7 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.58

Publications

2 publications found
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 Gene-Disease associations (from GenCC):
  • Lynch syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • Lynch syndrome 4
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • mismatch repair cancer syndrome 1
    Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • mismatch repair cancer syndrome 4
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • malignant pancreatic neoplasm
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • ovarian cancer
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • Muir-Torre syndrome
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • rhabdomyosarcoma
    Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
  • breast cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • prostate cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • hereditary breast carcinoma
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMS2NM_000535.7 linkc.610A>C p.Asn204His 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.610A>C p.Asn204His missense_variant Exon 6 of 15 1 NM_000535.7 ENSP00000265849.7 P54278-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Feb 27, 2015
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is denoted PMS2 c.610A>C at the cDNA level, p.Asn204His (N204H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant has been reported in an individual with a personal and/or family history of breast and/or ovarian cancer (Castera 2014). PMS2 Asn204His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. PMS2 Asn204His occurs at a position that is well conserved across vertebrates and is located in the ATPase domain (Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Asn204His is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Dec 21, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 418414). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 24549055). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 204 of the PMS2 protein (p.Asn204His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T;.;.;.;.;.
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D;.;D;.;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.82
D;D;D;D;D;D
MetaSVM
Uncertain
0.019
D
MutationAssessor
Uncertain
2.6
M;.;.;.;.;M
PhyloP100
7.6
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-4.4
D;D;.;.;.;D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D;D;.;.;.;T
Sift4G
Pathogenic
0.0
D;D;.;.;.;T
Polyphen
1.0
D;D;.;.;D;D
Vest4
0.92
MutPred
0.42
Gain of catalytic residue at L206 (P = 0.0764);.;.;.;.;Gain of catalytic residue at L206 (P = 0.0764);
MVP
0.91
MPC
0.28
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.85
gMVP
0.73
Mutation Taster
=0/100
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs746910555; hg19: chr7-6038834; API