ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4063A>G (p.Asn1355Asp) (rs876660530)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214543 SCV000278038 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-28 criteria provided, single submitter clinical testing
GeneDx RCV000483643 SCV000568986 uncertain significance not provided 2016-08-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4063A>G at the cDNA level, p.Asn1355Asp (N1355D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). Using alternate nomenclature, this variant would be defined as BRCA1 4182A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Asn1355Asp 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 Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Asn1355Asp occurs at a position that is not conserved and is located in the SCD domain and in a region known to interact with multiple proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Asn1355Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000557477 SCV000635938 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-02-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 1355 of the BRCA1 protein (p.Asn1355Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 233624). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000781029 SCV000918790 uncertain significance not specified 2018-10-29 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4063A>G (p.Asn1355Asp) 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 4.1e-06 in 245710 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.4063A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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