ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.735A>C (p.Arg245Ser) (rs375790538)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223222 SCV000278126 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000076994 SCV000488086 uncertain significance Breast-ovarian cancer, familial 2 2015-12-23 criteria provided, single submitter clinical testing
GeneDx RCV000657121 SCV000279927 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.735A>C at the cDNA level, p.Arg245Ser (R245S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGC). Using alternate nomenclature, this variant has been published as BRCA2 963A>C. This variant was observed in at least one individual with a personal history and family history of breast cancer, whose tumor showed no loss of heterozygosity (Sorscher 2017). BRCA2 Arg245Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Arg245Ser occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Arg245Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000476618 SCV000549698 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 245 of the BRCA2 protein (p.Arg245Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs375790538, ExAC 0.02%). 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: 91477). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214881 SCV000600744 uncertain significance not specified 2017-05-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000076994 SCV000108791 uncertain significance Breast-ovarian cancer, familial 2 2012-02-23 no assertion criteria provided clinical testing

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