ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6513_6514delinsCG (p.Ser2172Ala) (rs1064794089)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484681 SCV000567790 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6513_6514delGTinsCG at the cDNA level. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is AAGT[GT][CG]CACT. Using alternate nomenclature, this variant would be defined as BRCA2 6741_6742delGTinsCG. The deletion and insertion includes a G>C polymorphism, preserving a Valine at codon 2171, and an adjacent missense change of a Serine to an Alanine (TCA>GCA) at codon 2172. Neither BRCA2 c.6513_6514delGTinsCG nor BRCA2 Ser2171Ala have been published in the literature to our knowledge as pathogenic or benign. In addition, neither was 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. Since Serine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 c.6513_6514delGTinsCG occurs at a position that is not conserved and is not located in a known functional domain (Narod 2004, Roy 2012). In addition, in silico analyses for BRCA2 Ser2172Ala are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, we consider BRCA2 c.6513_6514delGTinsCG to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781046 SCV000918825 uncertain significance not specified 2018-02-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6513_6514delinsCG (p.Ser2172Ala) variant involves the alteration of a dinucleotide non-conserved sequence (GT>CG). Five out of five in silico analyses predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was not observed in 263870 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "uncertain significance." Note, the single nucleotide change, c.6514T>G, causes the same missense change and has been reported by a clinical diagnostic laboratory (ClinVar submission) and a reputable database as "uncertain significance." Based on the available evidence, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000538024 SCV000635513 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-17 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 2172 of the BRCA2 protein (p.Ser2172Ala). The serine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. 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: 419761). 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 alanine 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.

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