ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2726A>T (p.Asn909Ile) (rs80357127)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083429 SCV000075957 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132325 SCV000187412 likely benign Hereditary cancer-predisposing syndrome 2020-10-14 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
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 Breast neoplasm 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 Health, Inc RCV000132325 SCV000683058 benign Hereditary cancer-predisposing syndrome 2020-07-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235335 SCV000918690 likely benign not specified 2020-11-06 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2726A>T (p.Asn909Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 279764 control chromosomes, predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2726A>T has been reported in the literature in individuals of Asian ancestry who were affected by breast cancer, but was also found in healthy controls (e.g. Lai, 2017; Ahmadloo, 2017, Bhaskaran_2019, Kwong_2020, Momozawa_2018). In addition, a recent study classified this variant as likely benign based on a multifactorial probability model (Lee_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355281 SCV001550116 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asn909Ile variant was identified in 21 of 23988 proband chromosomes (frequency: 0.0009) from individuals or families with breast or ovarian cancer and was present in 18 of 25598 control chromosomes (frequency: 0.0007) from healthy individuals (Arai 2018, Bhaskaran 2019, Cao 2016, Chen 2003, Jang 2012, Lai 2017, Momozawa 2018, Thirthagiri 2008). The variant was also identified in dbSNP (ID: rs80357127) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae; and as uncertain significance by Ambry Genetics, GeneDx and seven other submitters), LOVD 3.0 (6x), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 20 of 245542 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 20 of 17248 chromosomes (freq: 0.001), increasing the likelihood this could be a low frequency benign variant, while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Asn909 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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