rs756312205
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000535.7(PMS2):c.803+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000474 in 1,264,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000535.7 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248408Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134238
GnomAD4 exome AF: 0.00000474 AC: 6AN: 1264626Hom.: 0 Cov.: 19 AF XY: 0.00000313 AC XY: 2AN XY: 638988
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 07, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 05, 2022 | This variant causes an A to G nucleotide substitution at the +4 position of intron 7 of the PMS2 gene. Splice site prediction tools are inconclusive on whether this variant has a significant impact on RNA splicing. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/248408 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
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 01, 2024 | The PMS2 c.803+4A>G variant has been reported in the published literature in individuals with prostate cancer (PMID: 29368341 (2018)) and personal and/or family history of breast and/or ovarian cancer (PMID: 31159747 (2019)). The frequency of this variant in the general population, 0.0000081 (2/248408 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 may affect proper PMS2 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 29, 2024 | This sequence change falls in intron 7 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs756312205, gnomAD 0.0009%). This variant has been observed in individual(s) with prostate cancer and/or personal or family history of hereditary breast and/or ovarian cancer (PMID: 29368341, 31159747). ClinVar contains an entry for this variant (Variation ID: 484256). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in Invitae (multiple RNA products). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at