Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000535.7(PMS2):c.*2C>G 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 Conflicting classifications of pathogenicity (no stars).
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: Likely_benign. The variant received -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP6
Variant 7-5973397-G-C is Benign according to our data. Variant chr7-5973397-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2774116.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000485
AC:
4
AN:
824220
Hom.:
0
Cov.:
11
AF XY:
0.00000467
AC XY:
2
AN XY:
428384
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
20774
American (AMR)
AF:
0.00
AC:
0
AN:
35570
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
20392
East Asian (EAS)
AF:
0.000128
AC:
4
AN:
31150
South Asian (SAS)
AF:
0.00
AC:
0
AN:
65954
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46172
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2988
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
563230
Other (OTH)
AF:
0.00
AC:
0
AN:
37990
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.040428), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
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
Cov.:
19
Alfa
AF:
0.00
Hom.:
0
ClinVar
Significance: Conflicting classifications of pathogenicity
This variant is located in the 3' untranslated region of the PMS2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/199490 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. -
Lynch syndrome 4Benign:1
Feb 04, 2025
Myriad Genetics, Inc.
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is considered benign. This variant occurs in the non-coding 3' untranslated region of the gene, and is not expected to impact protein function. -