7-5987062-G-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000535.7(PMS2):āc.1703C>Gā(p.Pro568Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251372Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135876
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727234
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
Lynch syndrome Uncertain:2
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This missense variant replaces proline with arginine at codon 568 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with peritoneal cancer with a family history of pancreatic, breast and lymphoma cancer (PMID: 26845104). This variant has been identified in 1/251372 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:2
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Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a patient with peritoneal cancer (Shirts et al., 2016); This variant is associated with the following publications: (PMID: 26845104) -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This missense variant replaces proline with arginine at codon 568 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with peritoneal cancer with a family history of pancreatic cancer, breast cancer, and lymphoma (PMID: 26845104). This variant has been identified in 1/251372 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. -
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. -
not specified Uncertain:1
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Hereditary nonpolyposis colorectal neoplasms Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 568 of the PMS2 protein (p.Pro568Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with primary peritoneal cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224585). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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. -
Lynch syndrome 4 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at