Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002229656 | SCV000286353 | uncertain significance | Mosaic variegated aneuploidy syndrome 1 | 2024-08-31 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 544 of the BUB1B protein (p.Pro544Ser). This variant is present in population databases (rs138332995, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BUB1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 238662). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
| Fulgent Genetics, |
RCV000765205 | SCV000896441 | uncertain significance | Mosaic variegated aneuploidy syndrome 1; Premature chromatid separation trait; Carcinoma of colon | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV002229656 | SCV002766991 | uncertain significance | Mosaic variegated aneuploidy syndrome 1 | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mosaic variegated aneuploidy syndrome 1 (MIM#257300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant as been reported as likely benign (LOVD) and as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Ambry Genetics | RCV003165612 | SCV003874881 | uncertain significance | Inborn genetic diseases | 2022-11-20 | criteria provided, single submitter | clinical testing | The p.P544S variant (also known as c.1630C>T), located in coding exon 14 of the BUB1B gene, results from a C to T substitution at nucleotide position 1630. The proline at codon 544 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV001357479 | SCV001552962 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The BUB1B p.Pro544Ser variant was not identified in the literature but was identified in dbSNP (ID: rs138332995) and ClinVar (classified as uncertain significance by Invitae and Fulgent Genetics). The variant was identified in control databases in 20 of 268202 chromosomes at a frequency of 0.00007457 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: European (non-Finnish) in 19 of 118100 chromosomes (freq: 0.000161) and African in 1 of 23590 chromosomes (freq: 0.000042), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Pro544 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |