ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.322A>C (p.Asn108His) (rs80358567)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113415 SCV001161579 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00136 (African), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV001079112 SCV000072166 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131576 SCV000186584 likely benign Hereditary cancer-predisposing syndrome 2020-05-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study;Structural Evidence;Subpopulation frequency in support of benign classification
GeneDx RCV000590284 SCV000210232 likely benign not provided 2019-04-29 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000590284 SCV000230001 uncertain significance not provided 2014-11-13 criteria provided, single submitter clinical testing
Counsyl RCV000113415 SCV000488864 uncertain significance Breast-ovarian cancer, familial 2 2016-07-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590284 SCV000600542 likely benign not provided 2019-10-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168534 SCV000694681 likely benign not specified 2020-08-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.322A>C (p.Asn108His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251048 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.3- fold the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.322A>C has been reported in the literature in individuals/families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Wagner_1999, Gao_2000, Diez_2003, Nanda_2005, Lu_2012). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been reported (BRCA1 c.3748G>T , p.Glu1250X; internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments (benign/likely benign, n=4; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000131576 SCV000903028 likely benign Hereditary cancer-predisposing syndrome 2016-06-30 criteria provided, single submitter clinical testing
Mendelics RCV000113415 SCV001138953 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113415 SCV000146588 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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