Our verdict is Benign. The variant received -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 (★★★).
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]
Our verdict: Benign. The variant received -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].
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
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.000107
AC:
2
AN:
18734
American (AMR)
AF:
0.000422
AC:
14
AN:
33172
Ashkenazi Jewish (ASJ)
AF:
0.000154
AC:
3
AN:
19454
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30864
South Asian (SAS)
AF:
0.0000961
AC:
6
AN:
62424
European-Finnish (FIN)
AF:
0.000283
AC:
13
AN:
45932
Middle Eastern (MID)
AF:
0.000337
AC:
1
AN:
2970
European-Non Finnish (NFE)
AF:
0.000721
AC:
335
AN:
464640
Other (OTH)
AF:
0.000583
AC:
20
AN:
34296
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.273
Heterozygous variant carriers
0
25
50
74
99
124
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000308
AC:
1
AN:
32514
American (AMR)
AF:
0.000514
AC:
6
AN:
11668
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3002
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3846
South Asian (SAS)
AF:
0.00
AC:
0
AN:
3470
European-Finnish (FIN)
AF:
0.000975
AC:
8
AN:
8208
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
252
European-Non Finnish (NFE)
AF:
0.000703
AC:
40
AN:
56936
Other (OTH)
AF:
0.000613
AC:
1
AN:
1632
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Jun 24, 2014
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Lynch syndrome 4Uncertain:1Benign:2
May 31, 2017
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This 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. -
Lynch syndromeBenign:2
Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance:Benign
Review Status:reviewed by expert panel
Collection Method:research
MAF >1% -
Oct 26, 2023
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Breast and/or ovarian cancerBenign:1
Apr 21, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
not providedBenign:1
Sep 24, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Hereditary cancer-predisposing syndromeBenign:1
Nov 18, 2014
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This 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. -