ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9257G>C (p.Gly3086Ala) (rs574271678)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580829 SCV000684044 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing
Counsyl RCV000144196 SCV000488053 uncertain significance Breast-ovarian cancer, familial 2 2015-12-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236803 SCV000592271 uncertain significance not specified 2014-11-18 criteria provided, single submitter clinical testing
GeneDx RCV000586031 SCV000293578 uncertain significance not provided 2015-11-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9257G>C at the cDNA level, p.Gly3086Ala (G3086A) at the protein level, and results in the change of a Glycine to an Alanine (GGA>GCA). Using alternate nomenclature, this variant would be defined as BRCA2 9485G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly3086Ala 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 Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Gly3086Ala occurs at a position that is not conserved and is located in the DNA binding domain (Borg 2010). 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 Gly3086Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586031 SCV000695228 likely benign not provided 2017-02-14 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9257G>C (p.Gly3086Ala) variant involves the alteration of a conserved first nucleotide in exon 25, with 5/5 in silico tools predicting a damaging outcome. 5/5 splice prediction tools via Alamut predict no significant impact on normal splicing. This prediction was confirmed by a functional study, Bras-Goldberg_2012), RT-PCR and sequencing analysis did not detect an aberrant splicing product. This variant was found in the large, broad control population, ExAC, with an allele frequency of 11/111424 (1/10129, 1 homozygote), predominantly in the South Asian cohort, 11/15716 (1/1428, 1 homozygote), which does exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Therefore, suggesting this variant is likely a benign polymorphism found predominantly in population(s) of South Asian origin. A meeting presentation, Bras-Goldberg_2012, identified the variant in an OvC pt, who also carried a pathogenic BRCA1 variant, c.3770_3771delAG (p.Glu1257GlyfsX9). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. Therefore, taking into account the high frequency in South Asians including a homozygote individual, the co-occurrence with a pathogenic BRCA1 variant, and the variant was indicated to not affect splicing, the variant of interest has been classified as "Likely Benign."
Invitae RCV000545556 SCV000635731 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 3086 of the BRCA2 protein (p.Gly3086Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant also falls at the first nucleotide of exon 25 of the BRCA2 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs574271678, ExAC 0.07%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 156179). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional 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.
Sharing Clinical Reports Project (SCRP) RCV000144196 SCV000189269 uncertain significance Breast-ovarian cancer, familial 2 2011-02-25 no assertion criteria provided clinical testing

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