ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4941C>A (p.Asn1647Lys) (rs80357302)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212188 SCV000210189 uncertain significance not provided 2014-02-26 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4941C>A at the cDNA level, p.Asn1647Lys (N1647K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAA). This variant was found in one study to have no protein folding defect, normal peptide binding activity and specificity, and normal trascriptional activity (Lee 2010). BRCA1 Asn1647Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is only moderately conserved throughout evolution and is located in BRCT1 domain (UniProt). In silico analyses predict this variant to have a benign effect on protein structure and function. Based on the currently available information, we consider BRCA1 Asn1647Lys to be a variant of uncertain significance.
Ambry Genetics RCV000162826 SCV000213310 likely benign Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),In silico models in agreement (benign)
Color RCV000162826 SCV000683228 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779911 SCV000916822 likely benign not specified 2018-11-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4941C>A (p.Asn1647Lys) results in a non-conservative amino acid change located in the BRCT domain superfamily of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245959 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4941C>A in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. Three independent functional studies reported the variant to have no protein folding defect, normal peptide binding activity and specificity, normal transcriptional activity (Lee_2010, Wood_2016), and functional HDR activity (Findlay_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as Likely Benign.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112429 SCV000145216 uncertain significance Breast-ovarian cancer, familial 1 1998-11-30 no assertion criteria provided clinical testing

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