chr13-32333294-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000059.4(BRCA2):c.1816C>T(p.Pro606Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign 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. P606A) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1816C>T | p.Pro606Ser | missense_variant | Exon 10 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.1447C>T | p.Pro483Ser | missense_variant | Exon 10 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.1816C>T | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000415 AC: 1AN: 240808Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130632
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1452994Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 722604
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Variant summary: The BRCA2 c.1816C>T (p.Pro606Ser) variant involves the alteration of a non-conserved nucleotide and is predicted to be damaging by 3/5 in silico tools. This variant is absent in 117916 control chromosomes from ExAC. This variant was found in one HBOC patient in literature without strong evidence for pathogenicity and they authors also classify it as a UV (unclassified variant). One internal sample carrying this variant also carries another possibly pathogenic variant BRCA1 c.2068_2082del15. Taken together, this variant is classified as Variant of Uncertain Significance -
- -
- -
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.P606S variant (also known as c.1816C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1816. The proline at codon 606 is replaced by serine, an amino acid with similar properties. This variant is also known as c.2044C>T and has been reported in the literature in an individual with a family history of hereditary breast and ovarian cancer (Esteban Cardeñosa E et al. Breast Cancer Res Treat, 2008 Nov;112:69-73) and in 2/60,466 breast cancer cases and 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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. -
Hereditary breast ovarian cancer syndrome Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 606 of the BRCA2 protein (p.Pro606Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18060494, 21520333). This variant is also known as 2044C>T. ClinVar contains an entry for this variant (Variation ID: 495434). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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