ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6796A>C (p.Asn2266His) (rs80358905)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045048 SCV000073061 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 2266 of the BRCA2 protein (p.Asn2266His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency). The variant has been reported in individuals with hereditary breast and ovarian cancer (HBOC) (PMID: 27376475) and it is present in the Breast Cancer Information Core (BIC) database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52184). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000766642 SCV000321478 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6796A>C at the cDNA level, p.Asn2266His (N2266H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 7024A>C. This variant has been observed in at least one individual with a personal and/or family history of breast and/or ovarian cancer (Schenkel 2016). BRCA2 Asn2266His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn2266His occurs at a position that is conserved through mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Asn2266His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000113643 SCV000487897 uncertain significance Breast-ovarian cancer, familial 2 2015-12-10 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000254921 SCV000592074 uncertain significance not specified 2012-12-05 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113643 SCV000146932 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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