ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.215A>G (p.Asn72Ser) (rs276174818)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043952 SCV000071965 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 72 of the BRCA2 protein (p.Asn72Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs276174818, ExAC 0.03%). This variant has been reported in individuals affected with breast cancer (PMID: 18627636, 22476429), and in an individual with ovarian cancer (Invitae). However, in that individual a pathogenic allele was also identified in BRCA1, which suggests that this c.215A>G variant was not the primary cause of disease. This variant is also known as 443A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 51251). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
GeneDx RCV000212202 SCV000210433 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.215A>G at the cDNA level, p.Asn72Ser (N72S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant, also denoted BRCA2 443A>G using alternate nomenclature, has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (Thirthagiri 2008, Lu 2012). However, this variant was not seen at a statistically higher incidence in breast cancer cases vs. controls (Lai 2017, Momozawa 2018). BRCA2 Asn72Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asn72Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000113284 SCV000488136 uncertain significance Breast-ovarian cancer, familial 2 2016-01-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562408 SCV000661174 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000562408 SCV000911190 likely benign Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113284 SCV000146391 uncertain significance Breast-ovarian cancer, familial 2 2010-09-18 no assertion criteria provided clinical testing
3DMed Clinical Laboratory Inc RCV000677865 SCV000804026 uncertain significance Infiltrating duct carcinoma of breast 2018-05-21 no assertion criteria provided clinical testing

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