ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.841G>A (p.Asp281Asn) (rs80359088)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081452 SCV000073525 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130406 SCV000185267 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000586972 SCV000566347 uncertain significance not provided 2018-03-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.841G>A at the cDNA level, p.Asp281Asn (D281N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). Using alternate nomenclature, this variant would be defined as BRCA2 1069G>A. This variant has been observed in individuals with lung and pancreatic cancer (Lu 2015, O'Reilly 2018). BRCA2 Asp281Asn was observed at an allele frequency of 0.039% (6/15144 alleles) in individuals of African ancestry in large population cohorts (Lek 2016). BRCA2 Asp281Asn is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available information, we consider BRCA2 Asp281Asn to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482899 SCV000600802 uncertain significance not specified 2017-05-12 criteria provided, single submitter clinical testing
Color RCV000130406 SCV000683965 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000482899 SCV000695151 uncertain significance not specified 2019-11-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.841G>A (p.Asp281Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 243274 control chromosomes (gnomAD). In addition, this variant was found in 3/2559 (0.0012) African American individuals who are older than 70 years and cancer free (FLOSSIES database). c.841G>A has been reported in the literature in individuals affected with lung cancer or pancreatic cancer (Lu_2015, Shindo_2017, Parry_2017, O'Reilly_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.4611_4612insG, p.Gln1537_Gln1538?fs; BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x likely benign, 5x VUS). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics,PreventionGenetics RCV000586972 SCV000805779 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077438 SCV000109236 likely benign Breast-ovarian cancer, familial 2 2012-03-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077438 SCV000145778 uncertain significance Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing

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