rs80359221
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP3BP6
The NM_000059.4(BRCA2):c.9477C>A(p.Phe3159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,916 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. F3159S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.9477C>A | p.Phe3159Leu | missense_variant | Exon 25 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.9108C>A | p.Phe3036Leu | missense_variant | Exon 25 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1535C>A | non_coding_transcript_exon_variant | Exon 24 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259 | n.*1535C>A | 3_prime_UTR_variant | Exon 24 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251178 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461748Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727180 show subpopulations
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74336 show subpopulations
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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The p.F3159L variant (also known as c.9477C>A), located in coding exon 24 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9477. The phenylalanine at codon 3159 is replaced by leucine, an amino acid with highly similar properties. In a study of 1854 high-risk BR/OV cancer families in Italy, this alteration was detected in 1 family (Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71).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. -
not specified Uncertain:1
Variant summary: BRCA2 c.9477C>A (p.Phe3159Leu) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. 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. The variant allele was found at a frequency of 4e-06 in 251178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9477C>A has been reported in the literature in the presumed heterozygous state in individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (Azzollini_2016, Fanale_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function in vitro. These results showed no damaging effect of this variant (example, Biswas_2023). The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 34178674, 19043619, 37922907). ClinVar contains an entry for this variant (Variation ID: 52847). 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 Uncertain:1
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3159 of the BRCA2 protein (p.Phe3159Leu). This variant is present in population databases (rs80359221, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27062684). ClinVar contains an entry for this variant (Variation ID: 52847). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at