NM_007294.4:c.2841A>T
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_007294.4(BRCA1):c.2841A>T(p.Lys947Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K947R) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Fanconi anemia, complementation group SInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 4Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461836Hom.: 0 Cov.: 53 AF XY: 0.00000138 AC XY: 1AN XY: 727208 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
The p.K947N variant (also known as c.2841A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 2841. The lysine at codon 947 is replaced by asparagine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary breast ovarian cancer syndrome Uncertain:1
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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 220648). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 947 of the BRCA1 protein (p.Lys947Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at