ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.280C>T (p.Pro94Ser)

gnomAD frequency: 0.00004  dbSNP: rs80358531
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129340 SCV000184104 likely benign Hereditary cancer-predisposing syndrome 2019-04-18 criteria provided, single submitter clinical testing Other data supporting benign classification
Invitae RCV000168018 SCV000218670 likely benign Hereditary breast ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000589736 SCV000228767 uncertain significance not provided 2014-09-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589736 SCV000296711 uncertain significance not provided 2021-03-19 criteria provided, single submitter clinical testing
GeneDx RCV000589736 SCV000321446 likely benign not provided 2020-12-14 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21120943, 19471317, 25348012, 29659569, 29928469, 32641407, 32123317)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254706 SCV000694632 likely benign not specified 2022-03-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.280C>T (p.Pro94Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251082 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.280C>T has been reported in the literature in individuals affected with breast or ovarian cancer and HBOC (example, Caux-Moncoutier_2009, Ortiz_2016, Maksimenko_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.5266dup, p.Gln1756fsX74 in UMD database), providing supporting evidence for a benign role. This variant had no effect in a study assessing allelic imbalance as an indirect measure of the impact of out-of-frame defects leading to reductions in the levels of mutant mRNA cleared through NMD (example, Caux-Moncoutier 2009). This supports the notion that this variant has no effect on splicing. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments some citing overlapping literature utilized in the context of this evaluation (likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000168018 SCV000838726 uncertain significance Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129340 SCV000910810 likely benign Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing
Mendelics RCV000031384 SCV001138950 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798039 SCV002042565 uncertain significance Breast and/or ovarian cancer 2020-09-30 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000254706 SCV002066668 uncertain significance not specified 2020-11-23 criteria provided, single submitter clinical testing DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.280C>T, in exon 3 that results in an amino acid change, p.Pro94Ser. This sequence change does not appear to have been previously described in patients with BRCA2-related disorders and has been described in the gnomAD database with a frequency of 0.014% in the Latino sub-population (dbSNP rs80358531). The p.Pro94Ser change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro94Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro94Ser change remains unknown at this time.
Sema4,Sema4 RCV000129340 SCV002535528 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-28 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031384 SCV000053989 benign Breast-ovarian cancer, familial, susceptibility to, 2 2012-03-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031384 SCV000146497 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000589736 SCV000591672 uncertain significance not provided no assertion criteria provided clinical testing The p.Pro94Ser variant was identified by Caux-Moncoutier (2009) in a hereditary breast/ovarian cancer (HBOC) patient. The authors of this study used an allelic imbalance assay to assess the putative impact of variants on splicing; no allelic imbalance was found for the variant, suggesting that it does not impact splicing. The variant was also identified in dbSNP (ID: rs80358531) “With non-pathogenic allele”, and three times in UMD as an unclassified variant. The p.Pro94 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Pro94Ser variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. 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 unknown significance.

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