ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4796A>G (p.Asn1599Ser) (rs149759218)

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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 RCV000222382 SCV000274711 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000230978 SCV000283249 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-05-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1599 of the BRCA2 protein (p.Asn1599Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 230992). 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 serine 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501254 SCV000591927 uncertain significance not specified 2012-10-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590510 SCV000694804 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4796A>G (p.Asn1599Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/120004 control chromosomes) but is present in gnomAD database (which includes ExAC and additional data from individuals undergoing whole genome sequencing) at an allele frequency of 0.01% (1/8734 chromosomes) in African subpopulation. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. However, it has been reported in UMD to co-occur with a premature truncating variant in BRCA1 gene c.2658insG (p.Ala887CysfsX16), suggesting non-pathogenic role of this variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance without evidence to independently evaluate. Based on the currently available information, this variant is classified as Variant of Unknown Significance.
Color RCV000222382 SCV000906091 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000238876 SCV000297530 uncertain significance Breast-ovarian cancer, familial 2 2009-05-13 no assertion criteria provided clinical testing

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