ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4037_4043delinsT (p.Thr1346_Cys1348delinsIle) (rs276174841)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130011 SCV000184836 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient evidence
Invitae RCV000229550 SCV000283224 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-06-22 criteria provided, single submitter clinical testing This sequence change deletes 7 nucleotides and inserts 1 nucleotide in exon 11 of the BRCA2 mRNA (c.4037_4043delCTGTTTGinsT). This leads to the deletion of 3 amino acid residues and an insertion of isoleucine in the BRCA2 protein (p.Thr1346_Cys1348delinsIle) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (no ExAC frequency). This variant has been reported in an individual with personal and/or family history of breast and ovarian cancer (PMID: 18418466). It is also known as 4265del7insT in the literature. ClinVar contains an entry for this variant (Variation ID: 126035). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the replaced amino acids is currently unknown. In summary, this variant is a rare in-frame change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000508118 SCV000605778 uncertain significance not specified 2017-05-26 criteria provided, single submitter clinical testing The p.Thr1346delinsIle variant in BRCA2 has been reported in 1 individual from a cohort of women with high risk of developing hereditary breast and ovarian canc er (Zhou 2005). It was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant has be en reported in ClinVar (Variation ID: 126035). This variant is an inframe deleti on of CTGTTTG and insertion T at position c.4037 and It is unclear if this delet ion/insertion will impact the protein. In summary, the clinical significance of the p.Thr1346delinsIle variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759609 SCV000889036 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing
Color RCV000130011 SCV000906469 likely benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000508118 SCV000916933 uncertain significance not specified 2018-03-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4037_4043delinsT (p.Thr1346_Cys1348delinsIle) results in an in-frame deletion that is predicted to remove 3 amino acids from the encoded protein and substitute them with Ile. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.4037_4043delinsT has been reported in the literature in individual(s) from high-risk HBOC family with calculated posterior probability 0.46 to be deleterious (Zhou_2005) as well as in a cancer-free individual older than 70 (FLOSSIES db). 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. Three 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) RCV000113263 SCV000146360 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113263 SCV000297525 uncertain significance Breast-ovarian cancer, familial 2 2008-05-17 no assertion criteria provided clinical testing

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