ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5249C>T (p.Ser1750Phe) (rs80358748)

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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 RCV000130265 SCV000185109 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113410 SCV000146582 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Color RCV000130265 SCV000906647 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing
Counsyl RCV000113410 SCV000785475 uncertain significance Breast-ovarian cancer, familial 2 2017-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000766556 SCV000569985 uncertain significance not provided 2016-04-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5249C>T at the cDNA level, p.Ser1750Phe (S1750F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). Using alternate nomenclature, this variant would be defined as/ has been previously published as BRCA2 5477C>T. This variant has been identified in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Gómez-García 2005). BRCA2 Ser1750Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser1750Phe occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ser1750Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000044619 SCV000072632 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 1750 of the BRCA2 protein (p.Ser1750Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs80358748, ExAC 0.003%). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 27062684, 15800311). ClinVar contains an entry for this variant (Variation ID: 51828). Algorithms developed to predict the effect of missense changes on protein structure and function 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483481 SCV000600635 uncertain significance not specified 2016-09-23 criteria provided, single submitter clinical testing

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