Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.1016A>G(p.Lys339Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K339N) has been classified as Likely benign.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Likely_benign. The variant received -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11218163).
BP6
Variant 17-43094515-T-C is Benign according to our data. Variant chr17-43094515-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 549761.
The p.K339R variant (also known as c.1016A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1016. The lysine at codon 339 is replaced by arginine, an amino acid with highly similar properties. This alteration was classified as likely benign by one study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 Jun;21:1435-1442). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Mar 23, 2023
University of Washington Department of Laboratory Medicine, University of Washington
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Hereditary breast ovarian cancer syndromeUncertain:1Benign:1
Apr 01, 2018
University of Washington Department of Laboratory Medicine, University of Washington
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research
The BRCA1 variant designated as c.1016A>G (p.Lys339Arg) is now classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of 0.20 to 1, which provides moderate evidence that this allele is not associated with similar risk compared to breast other cancer-associated variants in BRCA1. In addition, this variant alters a BRCA1 protein domain where the large majority of missense mutations are benign. This genomic position is not highly conserved. The combined results are consistent with a classification of likely benign. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a 2% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRCA1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
Oct 18, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 549761). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 339 of the BRCA1 protein (p.Lys339Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. -
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