7-5997374-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1

The NM_001322011.2(PMS2):​c.-179G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,606,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

PMS2
NM_001322011.2 5_prime_UTR_premature_start_codon_gain

Scores

1
10
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4

Conservation

PhyloP100: 3.32
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 Likely_benign. Variant got -5 ACMG points.

BP6
Variant 7-5997374-C-T is Benign according to our data. Variant chr7-5997374-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 455741.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000035 (51/1455614) while in subpopulation SAS AF= 0.000535 (46/85936). AF 95% confidence interval is 0.000412. There are 0 homozygotes in gnomad4_exome. There are 35 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
PMS2NM_000535.7 linkc.755G>A p.Cys252Tyr missense_variant Exon 7 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.755G>A p.Cys252Tyr missense_variant Exon 7 of 15 1 NM_000535.7 ENSP00000265849.7 P54278-1

Frequencies

GnomAD3 genomes
AF:
0.0000332
AC:
5
AN:
150482
Hom.:
0
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000835
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000719
AC:
18
AN:
250288
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135276
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.000527
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000350
AC:
51
AN:
1455614
Hom.:
0
Cov.:
30
AF XY:
0.0000483
AC XY:
35
AN XY:
724650
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000535
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.04e-7
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000332
AC:
5
AN:
150598
Hom.:
0
Cov.:
29
AF XY:
0.0000682
AC XY:
5
AN XY:
73342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000836
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000906
AC:
11
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Mar 02, 2018
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2025
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.755G>A (p.Cys252Tyr) results in a non-conservative amino acid change located in the DNA mismatch repair protein, C-terminal domain (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250288 control chromosomes, predominantly at a frequency of 0.00053 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05). c.755G>A has been reported in the literature in one individual affected with Breast Cancer, co-occurring with a pathogenic variant of PMS2 (Bhai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (PMS2 c.1908delA, p.Gln637fsX28), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 455741). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:2
Jun 28, 2022
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. -

Dec 11, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome Uncertain:1
Apr 16, 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 cysteine with tyrosine at codon 252 of the PMS2 protein. Computational prediction tool 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 18/250288 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:1
Sep 05, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484, 34326862) -

Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Uncertain:1
Jun 24, 2024
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 4 Uncertain:1
-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense variant in c.755G>A (p.Cys252Tyr) in PMS2 gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. The p.Cys252Tyr variant is reported with the allele frequency of 0.007192% in gnomAD Exome and is novel (not in any individuals) in 1000 Genomes. The amino acid Cys at position 252 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Cys252Tyr in PMS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Jan 26, 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
0.24
BayesDel_addAF
Benign
-0.058
T
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
T;.;.;.;.;.
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.92
D;D;.;D;.;D
M_CAP
Benign
0.057
D
MetaRNN
Uncertain
0.60
D;D;D;D;D;D
MetaSVM
Uncertain
0.58
D
MutationAssessor
Uncertain
2.6
M;.;.;.;.;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.7
D;D;.;.;.;D
REVEL
Uncertain
0.52
Sift
Benign
0.25
T;D;.;.;.;T
Sift4G
Benign
0.24
T;T;.;.;.;T
Polyphen
1.0
D;D;.;.;D;D
Vest4
0.64
MutPred
0.52
Gain of sheet (P = 0.0073);.;.;.;.;Gain of sheet (P = 0.0073);
MVP
0.96
MPC
0.31
ClinPred
0.90
D
GERP RS
5.5
Varity_R
0.78
gMVP
0.57

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs775445157; hg19: chr7-6037005; COSMIC: COSV56222962; COSMIC: COSV56222962; API