7-6003774-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001406875.1(PMS2):​c.-216C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PMS2
NM_001406875.1 5_prime_UTR_premature_start_codon_gain

Scores

13
4
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.51
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMS2NM_000535.7 linkc.269C>G p.Ser90Cys missense_variant Exon 4 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.269C>G p.Ser90Cys missense_variant Exon 4 of 15 1 NM_000535.7 ENSP00000265849.7 P54278-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000413
AC:
1
AN:
242162
Hom.:
0
AF XY:
0.00000756
AC XY:
1
AN XY:
132208
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1452496
Hom.:
0
Cov.:
29
AF XY:
0.00000277
AC XY:
2
AN XY:
723076
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000836
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Dec 13, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.S90C variant (also known as c.269C>G), located in coding exon 4 of the PMS2 gene, results from a C to G substitution at nucleotide position 269. The serine at codon 90 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Lynch syndrome 4 Uncertain:1
May 08, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.74
T;T
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Pathogenic
4.8
H;H
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-4.4
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.99
D;B
Vest4
0.96
MutPred
0.73
Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);
MVP
0.95
MPC
0.26
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.96
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs770678468; hg19: chr7-6043405; API