ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3362A>G (p.Asn1121Ser) (rs80356919)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048166 SCV000076179 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-13 criteria provided, single submitter clinical testing
Counsyl RCV000031108 SCV000489351 uncertain significance Breast-ovarian cancer, familial 1 2016-09-26 criteria provided, single submitter clinical testing
GeneDx RCV001697097 SCV000526285 likely benign not provided 2019-12-03 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26306726, 31131967)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000425661 SCV000600329 uncertain significance not specified 2016-10-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569556 SCV000660972 benign Hereditary cancer-predisposing syndrome 2015-02-05 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Health, Inc RCV000569556 SCV000903504 benign Hereditary cancer-predisposing syndrome 2016-09-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000425661 SCV001363930 uncertain significance not specified 2019-10-03 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3362A>G (p.Asn1121Ser) 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 1.6e-05 in 250354 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3362A>G has been reported in the literature at-least once in an individual affected with sporadic and/or familial Ovarian Cancer (Minucci_2015). 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. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; benign/likely benign, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286278 SCV001472820 uncertain significance none provided 2020-07-29 criteria provided, single submitter clinical testing The BRCA1 c.3362A>G; p.Asn1121Ser variant (rs80356919) is reported in the literature in an individual affected with ovarian cancer, but without a clear disease association (Minucci 2015). This variant is reported in ClinVar (Variation ID: 37527), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 1121 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, a multifactorial likelihood analysis categorized this variant as likely benign (Parsons 2019). However, given the lack of clinical and functional data, the significance of the p.Asn1121Ser variant is uncertain at this time. References: Minucci A et al. Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review. Expert Rev Mol Diagn. 2015;15(10):1383-1403. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019;40(9):1557-1578.
Research and Development, ARUP Laboratories RCV001659814 SCV001878303 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
Sharing Clinical Reports Project (SCRP) RCV000031108 SCV000053704 benign Breast-ovarian cancer, familial 1 2012-02-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031108 SCV000144739 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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