ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5813G>C (p.Gly1938Ala) (rs41293499)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129261 SCV000184021 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000129261 SCV000911399 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000168583 SCV000592003 likely benign not specified 2014-05-14 criteria provided, single submitter clinical testing
GeneDx RCV000657051 SCV000279422 uncertain significance not provided 2017-09-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5813G>C at the cDNA level, p.Gly1938Ala (G1938A) 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 6041G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly1938Ala was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Gly1938Ala occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). 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 Gly1938Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000168583 SCV000918976 uncertain significance not specified 2017-12-11 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5813G>C (p.Gly1938Ala) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/245820 control chromosomes (gnomAD) at a frequency of 0.0000163, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).
Invitae RCV000257904 SCV000549550 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 1938 of the BRCA2 protein (p.Gly1938Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs41293499, ExAC 0.01%). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91425). 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, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000076942 SCV000108739 likely benign Breast-ovarian cancer, familial 2 2012-07-23 no assertion criteria provided clinical testing

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