ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3211G>A (p.Glu1071Lys) (rs41293445)

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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 RCV000164153 SCV000214769 likely benign Hereditary cancer-predisposing syndrome 2020-08-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV001081229 SCV000259400 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-30 criteria provided, single submitter clinical testing
GeneDx RCV000255764 SCV000321428 uncertain significance not provided 2018-03-05 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3211G>A at the cDNA level, p.Glu1071Lys (E1071K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA1 3330G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu1071Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu1071Lys occurs at a position that is not conserved and is located in the DNA-binding domain (Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Glu1071Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000164153 SCV000903324 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-06 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 1071 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast and/or ovarian cancer (UMD database, Color internal data). A multifactorial analysis has reported this variant with posterior probability of being pathogenic of 0.004486 based in part to likelihood ratios for co-occurrence and health history of one family of 1.0331 and 0.2137, respectively (PMID: 31131967). This variant has been identified in 1/250450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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