chr7-5973396-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000535.7(PMS2):c.*3G>A 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).
Frequency
Consequence
NM_000535.7 3_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000867 AC: 10AN: 115298Hom.: 0 Cov.: 19
GnomAD3 exomes AF: 0.0000151 AC: 3AN: 199080Hom.: 1 AF XY: 0.0000277 AC XY: 3AN XY: 108398
GnomAD4 exome AF: 0.0000244 AC: 20AN: 818390Hom.: 2 Cov.: 11 AF XY: 0.0000211 AC XY: 9AN XY: 425600
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000867 AC: 10AN: 115298Hom.: 0 Cov.: 19 AF XY: 0.000109 AC XY: 6AN XY: 54944
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
The c.*3G>A variant is located in the 3' untranslated region (3’ UTR) of the PMS2 gene. This variant results from a G to A substitution 3 nucleotides downstream of the last translated codon. Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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 hereditary cancer in the literature. This variant has been identified in 5/219538 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequences in the PMS2CL pseudogene. 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 specified Uncertain:1Benign:1
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Variant summary: PMS2 c.*3G>A is located in the untranslated mRNA region downstream of the termination codon. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.5e-05 in 199080 control chromosomes in the gnomAD database, including 1 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.*3G>A in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 185828). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1Benign:1
The PMS2 c.*3G>A variant has not been reported in individuals with PMS2-related conditions in the published literature. The frequency of this variant in the general population, 0.000041 (4/96786 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect PMS2 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. -
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PMS2-related disorder Uncertain:1
The PMS2 c.*3G>A variant is located in the 3' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/185828/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary breast ovarian cancer syndrome Uncertain:1
no criteria applicable -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at