ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3965A>C (p.Asn1322Thr) (rs80358646)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165691 SCV000216429 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000483586 SCV000566175 uncertain significance not provided 2015-04-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3965A>C at the cDNA level, p.Asn1322Thr (N1322T) at the protein level, and results in the change of an Asparagine to a Threonine (AAC>ACC). Using alternate nomenclature, this variant would be defined as BRCA2 4193A>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1322Thr 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 Asparagine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Asn1322Thr occurs at a position that is not conserved across species and is not located in a known functional domain (UniProt). 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 Asn1322Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770722 SCV000902201 uncertain significance Breast and/or ovarian cancer 2017-01-06 criteria provided, single submitter clinical testing
Color RCV000165691 SCV000903955 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780038 SCV000917053 uncertain significance not specified 2018-11-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3965A>C (p.Asn1322Thr) results in a non-conservative amino acid change located in the BRCA2 repeat region, between the second and third repeat (IPR002093) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 224534 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3965A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483586 SCV001133777 uncertain significance not provided 2019-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113253 SCV000146347 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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