ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1343G>A (p.Arg448His) (rs80358423)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130010 SCV000184835 likely benign Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000587298 SCV000569844 uncertain significance not provided 2016-04-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1343G>A at the cDNA level, p.Arg448His (R448H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant, previously published as BRCA2 1571G>A, was identified in at least one individual with a personal and family history of breast cancer (Claes 2004). BRCA2 Arg448His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg448His occurs at a position that is not conserved and is not located in a known functional domain (Claes 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Arg448His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV001175372 SCV000694533 uncertain significance not specified 2019-10-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1343G>A (p.Arg448His) 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 2.4e-05 in 295704 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1343G>A has been reported in the literature in a family affected with breast cancer (Claes_2004). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Another study (Momozawa_2018) did not detect the variant in any of the breast cancer patients analyzed but detected it at a frequency of 0.00013 in controls who were 60 years old or over and did not have past history nor family history of cancers. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.2934T>G, p.Tyr978X; BIC database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and once as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000112910 SCV000785485 uncertain significance Breast-ovarian cancer, familial 2 2017-08-18 criteria provided, single submitter clinical testing
Color RCV000130010 SCV000911449 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587298 SCV001133676 uncertain significance not provided 2018-10-23 criteria provided, single submitter clinical testing
Mendelics RCV000112910 SCV001138996 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112910 SCV000145856 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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