chr17-43082585-C-T
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007294.4(BRCA1):c.4186-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,613,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007294.4 intron
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: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152106Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000279 AC: 70AN: 251002 AF XY: 0.000317 show subpopulations
GnomAD4 exome AF: 0.0000992 AC: 145AN: 1461636Hom.: 1 Cov.: 31 AF XY: 0.000127 AC XY: 92AN XY: 727130 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74422 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
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Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:2
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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not provided Benign:3
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Variant summary: The c.4186-10G>A in BRCA1 gene is an intronic change that involves a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC, mainly in individuals of East Asian descent at frequency of 0.17%, including one homozygous occurrence. The observed frequency exceeds the maximum expected allele frequency for a pathogenic BRCA1 variant, suggesting that it is a polymorphism. The fact that c.4186-10G>A has been reported to co-occur with two different deleterious mutation in BRCA1 gene (c.3700_3704delGTAAA and c.3759_3760delTA) suggests a non-disease causing nature of this variant. In addition, the variant has been reported as Polymorphismin published reports (Soumittra, 2009). Taken together, this variant has been classified as Benign. -
In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 18627636, 16267036, 25561518, 26269718, 28222693, 29280214) -
Hereditary cancer-predisposing syndrome Benign:2
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Hereditary breast ovarian cancer syndrome Benign:2
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Breast and/or ovarian cancer Benign:1
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BRCA1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Familial pancreatic carcinoma Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at