ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9906_9907delinsTT (p.Arg3302_Ser3303delinsSerCys) (rs876659538)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222145 SCV000276122 uncertain significance Hereditary cancer-predisposing syndrome 2015-05-26 criteria provided, single submitter clinical testing
GeneDx RCV000483519 SCV000564807 uncertain significance not provided 2015-01-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9906_9907delGAinsTT at the cDNA level and p.Arg3302_Ser3303delinsSerCys (R3302_S3303delinsSC) at the protein level. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is CAAG[GA][TT]GTTG. This in frame deletion and insertion, also denoted BRCA2 c.10134_10135delGAinsTT using alternate nomenclature, results in two adjacent missense changes, Arg3302Ser and Ser3303Cys,. While BRCA2 Ser3303Cys has been reported in at least one individual with breast cancer (Thirthagiri 2008), neither BRCA2 Arg3302Ser nor BRCA2 9906_9907delGAinsTT have, to our knowledge, been reported in the literature as pathogenic or benign. BRCA2 9906_9907delGAinsTT was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With regards to BRCA2 Arg3302Ser, since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution; this residue is highly conserved across species and in silico analyses predict that this variant is probably damaging to protein structure and function. With regards to BRCA2 Ser3303Cys, since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution; this residue is moderately conserved across species and in silico analyses predict that this variant is unlikely to alter protein structure or function. This variant is not located within a known functional domain (UniProt). Based on currently available information, it is unclear whether BRCA2 c.9906_9907delGAinsTT is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000234718 SCV000283375 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-13 criteria provided, single submitter clinical testing This variant, c.9906_9907delGAinsTT, is a complex sequence change that results in the in-frame exchange of 2 amino acids of the BRCA2 protein (p.Arg3302_Ser3303delinsSerCys). 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: 232077). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the exchanged amino acids is currently unknown. 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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