ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7307A>T (p.Asn2436Ile) (rs80358955)

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Total submissions: 8
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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) RCV000113744 SCV000244470 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000234
Invitae RCV000045184 SCV000073197 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000163011 SCV000213499 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
GeneDx RCV000429461 SCV000528561 likely benign not specified 2018-01-09 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.
Color RCV000163011 SCV000903131 benign Hereditary cancer-predisposing syndrome 2015-12-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000429461 SCV000918953 benign not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7307A>T (p.Asn2436Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 298704 control chromosomes in the gnomAD database. However, the variant was reported in some East Asian subpopulations with an even higher allele frequency, e.g. in the Japanese, with an allele frequency of 0.0039 (in the jMorp database). This frequency is about 5 fold higher than the maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00075), suggesting the variant could be a benign polymorphism found in population(s) from East Asia. The variant, c.7307A>T, has been reported in the literature in individuals of East Asian origin, who were affected with breast and/or ovarian cancer and fallopian tube carcinoma (Choi_2018, Kim_2017, Ikeda_2001). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two recent case-control association studies, involving breast cancer patients and controls of Korean (Park_2017) and Japanese ancestry (Momozawa_2018), found that the variant is not associated with a significant increase risk for breast/ovarian cancer, and therefore the authors of these studies classified the variant as likely benign/benign, respectively. In addition, IARC class based on posterior probability from multifactorial likelihood analysis suggests the variant to be benign (Lindor_2012, Easton_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign (2x) / benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000113744 SCV001139177 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113744 SCV000147066 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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