ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2726A>T (p.Asn909Ile) (rs80357127)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000657080 SCV000075957 likely benign not provided 2019-02-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132325 SCV000187412 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Michigan Medical Genetics Laboratories,University of Michigan RCV000031067 SCV000195910 uncertain significance Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240745 SCV000265879 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
GeneDx RCV000657080 SCV000293470 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2726A>T at the cDNA level, p.Asn909Ile (N909I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAT>ATT). Using alternate nomenclature, this variant has been previously published as BRCA1 2845A>T. This variant has been observed in individuals with a personal and/or family history of breast cancer, all of whom were of Asian ancestry, and was detected in 5/2091 breast cancer cases and 4/1462 controls in a study of multi-ethnic Asian individuals (Chen 2003, Thirthagiri 2008, Jang 2012, Cao 2016, Zhong 2016, Ahmadloo 2017, Arai 2017, Lai 2017, Park 2017). BRCA1 Asn909Ile was observed at an allele frequency of 0.12% (20/17,248) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in DNA binding domain and in a region reported to interact with RAD51 (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Asn909Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000031067 SCV000487963 uncertain significance Breast-ovarian cancer, familial 1 2015-12-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235335 SCV000600299 uncertain significance not specified 2016-12-05 criteria provided, single submitter clinical testing
Color RCV000132325 SCV000683058 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235335 SCV000918690 uncertain significance not specified 2017-09-11 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2726A>T (p.Asn909Ile) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have not been evaluated by functional studies. This variant was found in general population (gnomAD) at a frequency of 0.00008 (20/245542 control chromosomes), exclusively in the East Asian subpopulation at a frequency of 0.0011 (20/17248). This frequency is similar to the estimated maximal expected allele frequency of a pathogenic BRCA1 variant, suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant of interest has been reported in individuals of Asian ancestry who were affected by breast cancer, but was found also in healthy controls (Lai, 2017; Ahmadloo, 2017) with odds ratio suggesting the lack of strong association with disease. In addition, the variant was suspected to be a benign (Thirthagiri, 2008). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, the variant is classified as VUS-Possibly Benign, until additional information becomes available.
Sharing Clinical Reports Project (SCRP) RCV000031067 SCV000053663 uncertain significance Breast-ovarian cancer, familial 1 2012-06-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031067 SCV000144525 uncertain significance Breast-ovarian cancer, familial 1 1999-12-22 no assertion criteria provided clinical testing

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