ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2287C>G (p.His763Asp) (rs863224585)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200091 SCV000254173 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-07-31 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 763 of the BRCA2 protein (p.His763Asp). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. 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: 216240). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; 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.
Department of Pathology and Molecular Medicine,Queen's University RCV000496468 SCV000588082 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563152 SCV000668567 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing The p.H763D variant (also known as c.2287C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 2287. The histidine at codon 763 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000563152 SCV000906038 likely benign Hereditary cancer-predisposing syndrome 2017-09-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985474 SCV001133707 uncertain significance not provided 2019-01-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358320 SCV001554020 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.His763Asp variant was not identified in the literature nor was it identified in the LOVD 3.0 or UMD LSDB databases. The variant was identified in dSNP (rs863224585) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and COGR). The variant was identified in control databases in 1 of 30954 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Other population in 1 of 982 chromosomes (freq: 0.001), while the variant was not observed in the European, African, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.His763 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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