ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8765G>A (p.Ser2922Asn) (rs730881567)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222266 SCV000274058 uncertain significance Hereditary cancer-predisposing syndrome 2015-02-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000160156 SCV000592230 uncertain significance not specified 2012-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000656807 SCV000210483 uncertain significance not provided 2017-10-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8765G>A at the cDNA level, p.Ser2922Asn (S2922N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). Using alternate nomenclature, this variant would be defined as BRCA2 8993G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser2922Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ser2922Asn occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Ser2922Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000160156 SCV000919035 uncertain significance not specified 2018-12-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8765G>A (p.Ser2922Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245288 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8765G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000168175 SCV000218838 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 2922 of the BRCA2 protein (p.Ser2922Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182254). 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.

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