ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4339C>A (p.Gln1447Lys) (rs80357067)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759540 SCV000210174 uncertain significance not provided 2014-06-05 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4339C>A at the cDNA level, p.Gln1447Lys (Q1447K) at the protein level, and results in the change of a Glutamine to a Lysine (CAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gln1447Lys 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. Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Gln1447Lys occurs at a position that is well conserved across mammalian species with Lysine being the naturally occurring amino acid in one mammal. It is not located in a known functional domain. In addition, in silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Gln1447Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000457370 SCV000549315 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 1447 of the BRCA1 protein (p.Gln1447Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182161). 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 and their clinical significance is uncertain. 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.
Ambry Genetics RCV000570241 SCV000660998 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759540 SCV000888919 uncertain significance not provided 2018-06-23 criteria provided, single submitter clinical testing
Color RCV000570241 SCV000911083 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193114 SCV001361734 uncertain significance not specified 2019-07-24 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4339C>A (p.Gln1447Lys) results in a 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 4e-06 in 251344 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.4339C>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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