ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5095G>A (p.Asp1699Asn) (rs80358731)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081347 SCV000072565 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130358 SCV000185209 likely benign Hereditary cancer-predisposing syndrome 2019-03-07 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
GeneDx RCV000590213 SCV000526371 likely benign not provided 2020-05-15 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19912264, 22752604, 28692054, 26580448, 30555256, 31131967)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590213 SCV000694827 benign not provided 2016-03-21 criteria provided, single submitter clinical testing
Counsyl RCV000031527 SCV000786230 likely benign Breast-ovarian cancer, familial 2 2018-03-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130358 SCV000902797 likely benign Hereditary cancer-predisposing syndrome 2015-08-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590213 SCV001133816 benign not provided 2019-02-15 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642360 SCV001854824 uncertain significance Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031527 SCV000054132 likely benign Breast-ovarian cancer, familial 2 2012-03-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031527 SCV000146533 uncertain significance Breast-ovarian cancer, familial 2 2001-02-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000590213 SCV000591939 likely benign not provided no assertion criteria provided clinical testing The p.Asp1699Asn variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), GeneInsight COGR, COSMIC, MutDB, ARUP laboratories or LOVD databases. The p.Asp1699Asn variant was identified in dbSNP (ID: rs80358731 “With other allele”, with a minor allele frequency of 0.0006 (3 of 5000 chromosomes in1000 Genomes Project). This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Jan 13th, 2015) in 64 of 118544 chromosomes (frequency: 0.0005399) or 62 of 15484 alleles from a population of South Asians with 1 homozygous, 2 of 884 alleles of other populations and was not found in European (Non-Finnish), East Asian, African, Latino, European (Finnish) and individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified by our laboratory in 2 individuals with ovarian and breast cancers. The ClinVar database had conflicting interpretations: classified as a likely benign variant by the Sharing Clinical Reports Project, (derived from Myriad reports), by Invitae and Ambry Genetics whereas BIC classified the variant as uncertain significance. The BRCA Share UMD database classified the variant as unknown. In-silico splicing predictors do not predict any difference in splicing. The p.Asp1699 residue is not conserved in mammals and 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 amino acid Asparagine (Asn) is present in Cows, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as Likely Benign.

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