ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.745A>T (p.Thr249Ser)

dbSNP: rs397507256
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221443 SCV000276308 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-25 criteria provided, single submitter clinical testing The p.T249S variant (also known as c.745A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 745. The threonine at codon 249 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590556 SCV000699298 uncertain significance not provided 2017-06-08 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.745A>T (p.Thr249Ser) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant is absent in 120310 control chromosomes (ExAC). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertian Significance (VUS),"until additional information becomes available.
Color Diagnostics, LLC DBA Color Health RCV000221443 SCV000909399 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-22 criteria provided, single submitter clinical testing
Invitae RCV001063586 SCV001228440 uncertain significance Hereditary breast ovarian cancer syndrome 2023-05-07 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 37696). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 249 of the BRCA1 protein (p.Thr249Ser).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000590556 SCV003799795 uncertain significance not provided 2022-03-11 criteria provided, single submitter clinical testing The BRCA1 c.745A>T; p.Thr249Ser variant (rs397507256), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 37696). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 249 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.568). Due to limited information, the clinical significance of the p.Thr249Ser variant is uncertain at this time.
University of Washington Department of Laboratory Medicine, University of Washington RCV000221443 SCV003847972 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP) RCV000031277 SCV000053882 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2010-05-10 no assertion criteria provided clinical testing

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