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

gnomAD frequency: 0.00003  dbSNP: rs80356919

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048166	SCV000076179	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000031108	SCV000489351	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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	RCV001697097	SCV000600329	uncertain significance	not provided	2024-12-04	criteria provided, single submitter	clinical testing	The BRCA1 c.3362A>G (p.Asn1121Ser) variant has been reported in the published literature in an individual with ovarian cancer (PMID: 26306726 (2015)). A multifactorial analysis study has reported that this variant is likely not pathogenic (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.000016 (4/250354 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
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: seen in unaffected individuals, 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 Diagnostics, LLC DBA Color Health	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	RCV001697097	SCV001472820	uncertain significance	not 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.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000048166	SCV002025958	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000569556	SCV002538202	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-19	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000569556	SCV003851987	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000048166	SCV004228139	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-26	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031108	SCV000053704	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-02-24	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031108	SCV000144739	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing