ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4376A>G (p.Asn1459Ser) (rs117187202)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677823 SCV000803983 uncertain significance Invasive Lobular Breast Carcinoma 2017-02-27 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677824 SCV000803984 uncertain significance Ovarian cancer 2017-02-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000166927 SCV000217746 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000031479 SCV000146415 uncertain significance Breast-ovarian cancer, familial 2 2010-09-18 no assertion criteria provided clinical testing
Color RCV000166927 SCV000911008 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
Counsyl RCV000031479 SCV000487988 uncertain significance Breast-ovarian cancer, familial 2 2015-12-10 criteria provided, single submitter clinical testing
GeneDx RCV000481899 SCV000568107 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4376A>G at the cDNA level, p.Asn1459Ser (N1459S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). Using alternate nomenclature, this variant would be defined as BRCA2 4604A>G. This variant has been observed in individuals with breast or ovarian cancer in Asian populations, but has also been observed in controls (Suter 2004, Chao 2016, Zhong 2016. Lai 2017, Li 2017). BRCA2 Asn1459Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Asn1459Ser is located in the domain that interacts with RAD51 and POLH (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Asn1459Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000044400 SCV000072413 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-01 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1459 of the BRCA2 protein (p.Asn1459Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs117187202, ExAC 0.03%). This variant has been reported in individuals affected with breast cancer (PMID: 14973102, 27257965, 28222693, 28664449), and an individual affected with ovarian cancer (PMID: 27907908). ClinVar contains an entry for this variant (Variation ID: 37898). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240790 SCV000265940 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Sharing Clinical Reports Project (SCRP) RCV000031479 SCV000054084 uncertain significance Breast-ovarian cancer, familial 2 2009-12-02 no assertion criteria provided clinical testing

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