ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5017A>C (p.Thr1673Pro)

dbSNP: rs746274489
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000509933 SCV000608168 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-28 criteria provided, single submitter clinical testing The p.T1673P variant (also known as c.5017A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 5017. The threonine at codon 1673 is replaced by proline, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6475 samples (12950 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0004% (greater than 225000 alleles tested) in our clinical cohort. This amino acid position is 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001299174 SCV001488253 uncertain significance Hereditary breast ovarian cancer syndrome 2020-03-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 1673 of the BRCA2 protein (p.Thr1673Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 441467). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000509933 SCV003852283 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).

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