chr17-43092261-T-A
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B.
The NM_007294.4(BRCA1):c.3270A>T(p.Gln1090His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Q1090R) has been classified as Likely benign.
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 AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000798 AC: 2AN: 250594 AF XY: 0.00000738 show subpopulations
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461540Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2AN XY: 727076 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
This missense variant replaces glutamine with histidine at codon 1090 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported by ENIGMA with a tumor pathology likelihood ratio of 0.64 (PMID: 31131967) and has been observed in an individual affected with breast cancer (Color internal data). This variant has been identified in 3/281990 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. -
The p.Q1090H variant (also known as c.3270A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 3270. The glutamine at codon 1090 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:2
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not specified Uncertain:1
Variant summary: BRCA1 c.3270A>T (p.Gln1090His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245324 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.3270A>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
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Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at