ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4024A>G (p.Ser1342Gly) (rs1060502476)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564249 SCV000666008 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000662790 SCV000785600 uncertain significance Breast-ovarian cancer, familial 2 2017-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000481471 SCV000566807 uncertain significance not provided 2015-06-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4024A>G at the cDNA level, p.Ser1342Gly (S1342G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 4252A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser1342Gly 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. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser1342Gly occurs at a position that is not conserved and is located within the region of interaction with POLH (UniProt). While protein-based in silico analyses predict that this variant is unlikely to alter protein structure or function, multiple splicing models predict that this variant might create a cryptic splice donor site and possibly lead to abnormal splicing. Based on currently available information, it is unclear whether BRCA2 Ser1342Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000476675 SCV000549822 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 1342 of the BRCA2 protein (p.Ser1342Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. 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: 409576). 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 glycine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.

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