13-32338616-T-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):āc.4261T>Cā(p.Phe1421Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,444,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4261T>C | p.Phe1421Leu | missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.3892T>C | p.Phe1298Leu | missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.4261T>C | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000623 AC: 9AN: 1444770Hom.: 0 Cov.: 35 AF XY: 0.00000559 AC XY: 4AN XY: 715552
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
The p.F1421L variant (also known as c.4261T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 4261. The phenylalanine at codon 1421 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is poorly 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. -
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces phenylalanine with leucine at codon 1421 of the BRCA2 protein (p.Phe1421Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance. The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at