ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2122T>A (p.Ser708Thr) (rs80358488)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043947 SCV000071960 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-08-25 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 708 of the BRCA2 protein (p.Ser708Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs80358488, ExAC 0.06%). This variant has been reported in an individual with breast cancer, and individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51246). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000130632 SCV000185508 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000216194 SCV000279893 uncertain significance not provided 2018-04-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2122T>A at the cDNA level, p.Ser708Thr (S708T) at the protein level, and results in the change of a Serine to a Threonine (TCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 2350T>A. This variant was observed in at least one patient with breast cancer (Suter 2004). BRCA2 Ser708Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser708Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000113017 SCV000785073 uncertain significance Breast-ovarian cancer, familial 2 2017-03-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763881 SCV000894816 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000130632 SCV000903950 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194412 SCV001363948 uncertain significance not specified 2019-07-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2122T>A (p.Ser708Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250964 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2122T>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and colon cancer (Chan_2018, Dong_2018, Li_2018, Lu_2015, Suter_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113017 SCV000146008 uncertain significance Breast-ovarian cancer, familial 2 2000-07-07 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735530 SCV000863668 uncertain significance Breast and/or ovarian cancer 2001-05-08 no assertion criteria provided clinical testing

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