Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genomic Diagnostic Laboratory, |
RCV000239355 | SCV000296934 | likely benign | not specified | 2015-07-27 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000555261 | SCV000625595 | benign | Hereditary nonpolyposis colorectal neoplasms | 2024-01-31 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000567860 | SCV000663438 | benign | Hereditary cancer-predisposing syndrome | 2017-11-17 | criteria provided, single submitter | clinical testing | This alteration is classified as benign based on a combination of the following: 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000239355 | SCV000697337 | benign | not specified | 2021-07-12 | criteria provided, single submitter | clinical testing | Variant summary: PMS2 c.2182A>G (p.Thr728Ala) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 229692 control chromosomes, predominantly at a frequency of 0.029 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 408.31 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2182A>G has been reported in the literature in individuals. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. |
University of Washington Department of Laboratory Medicine, |
RCV000758628 | SCV000887385 | likely benign | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | PMS2 NM_000535.5:c.2182A>G has a 2.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. |
CHEO Genetics Diagnostic Laboratory, |
RCV001798624 | SCV002042797 | benign | Breast and/or ovarian cancer | 2020-06-18 | criteria provided, single submitter | clinical testing | |
Center for Genomic Medicine, |
RCV000239355 | SCV002550692 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Pathway Genomics | RCV000172820 | SCV000223786 | uncertain significance | Lynch syndrome 1 | 2014-10-30 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001357402 | SCV001552869 | benign | Malignant tumor of breast | no assertion criteria provided | clinical testing | The PMS2 p.Thr728Ala variant was identified in 1 of 192 proband chromosomes (frequency: 0.005) from individuals with pancreatic cancer (Hu 2016). The variant was identified in dbSNP (rs141893001) as “with uncertain significance allele” and ClinVar (classified as benign by Invitae, Ambry Genetics and VU University, likely benign by The Children's Hospital of Philadelphia and the University of Washington and uncertain significance by Integrated Genetics and Pathway Genomics). The variant was identified in control databases in 668 of 260,078 chromosomes (5 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 582 of 21,634 chromosomes (freq: 0.03), Other in 16 of 6782 chromosomes (freq: 0.002), Latino in 46 of 34,228 chromosomes (freq: 0.001), Ashkenazi Jewish in 3 of 9896 chromosomes (freq: 0.0003), European in 20 of 115,888 chromosomes (freq: 0.0002), South Asian in 1 of 28,826 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian, and Finnish populations. The p.Thr728Ala residue is not conserved in mammals and four out of five 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. |