ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4776C>G (p.Asn1592Lys) (rs761925468)

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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 RCV000162819 SCV000213302 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000590715 SCV000567561 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4776C>G at the cDNA level, p.Asn1592Lys (N1592K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 4895C>G. Although this exact nucleotide change has not, to our knowledge, been published in the literature as pathogenic or benign, a different nucleotide change at the same position resulting in the same amino acid change was observed in a cohort of 121 Moroccan breast cancer patients (Laraqui 2013). BRCA1 Asn1592Lys was not observed at a significant frequency in large population cohorts (Lek 2016). Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Asn1592Lys occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is located in a region known to interact with multiple proteins (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 Asn1592Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000485047 SCV000591538 uncertain significance not specified 2015-01-19 criteria provided, single submitter clinical testing
Color RCV000162819 SCV000683213 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000485047 SCV000699175 uncertain significance not specified 2019-01-17 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA1 c.4776C>G (p.Asn1592Lys) 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 1.2e-05 in 246144 control chromosomes (gnomAD). 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.4776C>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. However, another variant, c.4776C>A, which causes the same protein change was reported in 1 patient without strong evidence for causality (Laraqui_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (uncertain significance X5 and benign X1). Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000616786 SCV000744609 likely benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000697143 SCV000825739 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1592 of the BRCA1 protein (p.Asn1592Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs761925468, ExAC 0.009%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 183931). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000616786 SCV000733606 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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