ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3211C>T (p.His1071Tyr) (rs80358564)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212225 SCV000210310 uncertain significance not provided 2014-10-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3211C>T at the cDNA level, p.His1071Tyr (H1071Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant has been reported in the Breast Cancer Information Core (BIC) database as having unknown clinical importance. BRCA2 His1071Tyr 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 Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 His1071Tyr occurs at a position that is highly variable across species and is located in the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 His1071Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000113148 SCV000489593 uncertain significance Breast-ovarian cancer, familial 2 2016-10-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572282 SCV000661193 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Color Health, Inc RCV000572282 SCV000903952 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-11 criteria provided, single submitter clinical testing
Invitae RCV001299345 SCV001488430 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-02 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 1071 of the BRCA2 protein (p.His1071Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs80358564, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with pancreatic cancer (PMID: 28767289, 29309945). ClinVar contains an entry for this variant (Variation ID: 51424). 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 tyrosine 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. 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113148 SCV000146191 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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