chr7-5973382-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000535.7(PMS2):​c.*17G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 19)
Exomes 𝑓: 0.00055 ( 95 hom. )
Failed GnomAD Quality Control

Consequence

PMS2
NM_000535.7 3_prime_UTR

Scores

2

Clinical Significance

Benign reviewed by expert panel U:1B:10

Conservation

PhyloP100: -0.371
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 Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 7-5973382-C-G is Benign according to our data. Variant chr7-5973382-C-G is described in ClinVar as [Benign]. Clinvar id is 91277.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5973382-C-G is described in Lovd as [Benign]. Variant chr7-5973382-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PMS2NM_000535.7 linkuse as main transcriptc.*17G>C 3_prime_UTR_variant 15/15 ENST00000265849.12 NP_000526.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PMS2ENST00000265849.12 linkuse as main transcriptc.*17G>C 3_prime_UTR_variant 15/151 NM_000535.7 ENSP00000265849 P3P54278-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
56
AN:
122252
Hom.:
0
Cov.:
19
FAILED QC
Gnomad AFR
AF:
0.0000308
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000514
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000975
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000702
Gnomad OTH
AF:
0.000620
GnomAD3 exomes
AF:
0.0000385
AC:
7
AN:
181594
Hom.:
2
AF XY:
0.0000305
AC XY:
3
AN XY:
98252
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000201
Gnomad ASJ exome
AF:
0.000122
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000127
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000553
AC:
394
AN:
712486
Hom.:
95
Cov.:
9
AF XY:
0.000525
AC XY:
197
AN XY:
375338
show subpopulations
Gnomad4 AFR exome
AF:
0.000107
Gnomad4 AMR exome
AF:
0.000422
Gnomad4 ASJ exome
AF:
0.000154
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000961
Gnomad4 FIN exome
AF:
0.000283
Gnomad4 NFE exome
AF:
0.000721
Gnomad4 OTH exome
AF:
0.000583
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000458
AC:
56
AN:
122320
Hom.:
0
Cov.:
19
AF XY:
0.000408
AC XY:
24
AN XY:
58782
show subpopulations
Gnomad4 AFR
AF:
0.0000308
Gnomad4 AMR
AF:
0.000514
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000975
Gnomad4 NFE
AF:
0.000703
Gnomad4 OTH
AF:
0.000613
Alfa
AF:
0.00218
Hom.:
11

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:10
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jun 24, 2014- -
Lynch syndrome 4 Uncertain:1Benign:2
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterMay 31, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioApr 21, 2021- -
Lynch syndrome Benign:1
Benign, reviewed by expert panelresearchInternational Society for Gastrointestinal Hereditary Tumours (InSiGHT)Sep 05, 2013MAF >1% -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 23, 2023- -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 18, 2014This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
1.3
DANN
Benign
0.59

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: rs556089649; hg19: chr7-6013013; API