ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7661G>A (p.Ser2554Asn) (rs398122588)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160136 SCV000210439 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7661G>A at the cDNA level, p.Ser2554Asn (S2554N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). Using alternate nomenclature, this variant would be defined as BRCA2 7889G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser2554Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ser2554Asn occurs at a position that is conserved across species and is located within the SHFM1 binding domain and within the DSS1 contacting residue of DNA binding domain (Marston 1999, Yang 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ser2554Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000215704 SCV000274314 uncertain significance Hereditary cancer-predisposing syndrome 2015-03-06 criteria provided, single submitter clinical testing
Invitae RCV000637761 SCV000759238 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-09-05 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 2554 of the BRCA2 protein (p.Ser2554Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs398122588, ExAC 0.009%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91489). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000160136 SCV001148992 uncertain significance not provided 2018-12-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077006 SCV000108803 uncertain significance Breast-ovarian cancer, familial 2 2007-08-27 no assertion criteria provided clinical testing

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