ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5171T>C (p.Ile1724Thr) (rs80358743)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044591 SCV000072604 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000985249 SCV000108619 likely benign not provided 2020-12-14 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24817641, 26295337, 30212499, 28301460, 29906251)
Ambry Genetics RCV000131403 SCV000186379 likely benign Hereditary cancer-predisposing syndrome 2018-01-17 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985249 SCV000296509 uncertain significance not provided 2020-05-24 criteria provided, single submitter clinical testing
Counsyl RCV000113393 SCV000488145 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131403 SCV000903516 likely benign Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074534 SCV000918852 uncertain significance not specified 2021-06-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5171T>C (p.Ile1724Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 244828 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5171T>C has been reported in the literature in individuals affected with lung cancer and esophageal squamous cell carcinoma (Pietanza_2018, Ko_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely benign (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Research and Development, ARUP Laboratories RCV001646367 SCV001854830 likely benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA2) RCV000113393 SCV000146557 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353973 SCV000591948 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Ile1724Thr variant has been previously reported in the BIC database with unknown clinical significance in three individuals; it has also been identified in one individual with a clinical history of breast/ovarian cancer by our laboratory. This residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. This variant is listed in dbSNP with no frequency information (ID#:rs80358743). Another variant at the same amino acid position (c.5170A>G p.Ile1724Val) is listed as a polymorphism in dbSNP rs35335654 with an average heterozygosity of 0.027+/-0.112, increasing the likelihood the p.Ile1724Thr variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign.

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